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437 Cards in this Set
- Front
- Back
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America's rank in sugar intake and why?
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4th; soda
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proposed limit for added sugar per day in a 2000 calorie diet (grams per day)?
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40 g per day which is 8%
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Single most effective way to prevent childhood obesity
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limit children's intake of soft drinks and other sugar sweetened beverages
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What has been replacing the decreased fat intake of Americans?
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sugar
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What is glycemic index?
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a measurement created to help diabetics control their blood sugar. It represents carbs effects on blood sugar. Low= slow= good
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How does a high glycemic index lead to excess triglycerides formation?
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more glucose in the blood drives more glucose into the liver. This pushes triglyceride formation in the liver
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Why is pantothenic acid a critical vitamin for fatty acid synthesis?
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aka B5 which is a vit rarely deficient in Americans is an essential part of coenzyme A. Coenzyme A is an acetyl group, beta- mercaptoethanolamine, pantothenic acid, and ADP.
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Rate limiting enzyme for fatty acid synthesis
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acetyl coA carboxylase which facilitates a 2 step shuttle that concerts acetyl-CoA coming from the citrate shuttle to malonyl CoA
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What vitamin is essential for acetyl CoA carboxylase?
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biotin
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Where is acetyl-CoA carboxylase located?
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cytoplasm
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How is acetyl-CoA carboxylase inhibited?
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polymerized state is most active
phosphorylation promotes depolymerization AMP activate AMP-dependent kinase to phosphorylate acetyl CoA carboxylase cAMP dependent kinase phosphorylates the enzyme glucagon and E inhibit gene expression Palmitoyl CoA feeds back to transform the acetyl CoA carboxylase from the polymerized state to the monomer state |
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Stimulation of Acetyl CoA carboxylase.
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citrate- feeds forward to promote the formation of the polymerized enzyme
insulin- activates a phosphatase to put the enzyme in an unphosphorylated state so that it can polymerize to the active state; increases gene expression for the enzyme |
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What is palmitic acid formed from?
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acetyl CoA primer then malonyl CoA until you get 16 carbons. Uses a multienzyme complex called fatty acid synthase. It is a 4 step process.
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What is the primary carbon source?
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1. glucose
2. fructose 3. amino acids |
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Which sources are capable of driving fa synthesis in the liver?
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glucose & fructose
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How is fatty acid synthesis regulated?
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through gene expression
Insulin and glucose makes more fa synthase Glucagon and polyunsaturated FAs inhibits gene expression All regulation comes from the sterol response element binding protein (SREBP-1) which binds to DNA and turns on gene expression. |
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What regulates fatty acid synthesis in adipose tissue?
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insulin, glucagon, glucose, and leptin
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What is leptin?
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Leptin is a peptide hormone produced by adipose tissue that lowers SREBP-1 levels to reduce FA synthesis
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Where are fatty acids synthesized?
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In every cell in the body that has a mitochondria.
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What are the major sites of fatty acid synthesis?
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liver and adipose. Mammary glands when milk is being produced.
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What is the main control of fatty acid synthesis in adipose tissue?
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leptin and also works in other tissues
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Where do polyunsaturated fatty acids work to control fatty acid synthesis?
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liver but they can work in other tissues too
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Fatty acid synthesis is primarily under what type of control?
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gene control
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What is the first step in fatty acid synthesis?
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condensation which happens to an activated acyl group with CH2-carbon malonyl CoA, releasing malonyl CoA's free COO- group as CO2. Every condensation reaction that occurs after, only malonyl CoA is added.
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What is the second step in fatty acid synthesis?
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Reduction- of the beta keto group of an alcohol. Use NADPH
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What is the third step in fatty acid synthesis?
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dehydration- elimination of water to create a double bond
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What is the fourth step in fatty acid synthesis?
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Reduction of a double bond to create saturated fatty acyl group with the use of NADPH.
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What are the 6 enzymes in the citrate shuttle?
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ATP citrate lyase
Malate dehydrogenase malic enzyme pyruvate decarboxylase pyruvate dehydrogenase citrate synthase |
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What does ATP citrate lyase do?
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converts citrate to oxaloacetate with the addition of ATP and CoASH
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What does malate dehydrogenase do?
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NADH + oxaloacetate makes NAD and malate
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What does malic enzyme do?
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malate and NADP form CO2, NADPH, and pyruvate
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What does pyruvate carboxylase do?
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pyruvate, HCO3-, and ATP form oxaloacetate, ADP, and phosphate
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What does pyruvate dehydrogenase do?
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NADH, CoASH, and pyruvate form NADH and acetyl CoA
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What does citrate synthase do?
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converts both oxaloacetate and acetyl CoA to citrate
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Where does the citrate come from?
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mitochondria and is used to drive FA synthesis in the cytoplasm
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Where does the malate come from?
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oxaloacetate. In the mitochondria, malate produces oxaloacetate
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What shuttle provides cytosolic acetate units and reducing equivalents for FA synthesis?
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citrate- malate- pyruvate shuttle
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List 3 enzymes that form NADPH that are needed for fatty acid synthesis and their location.
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malic enzyme (citrate shuttle), glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase (last two from the pentose phosphate pathway)
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What enzyme generates NADPH for the fatty acid synthase complex?
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malic enzyme
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What induces G6PD (glucose 6 phosphate dehydrogenase) and what pathways is this enzyme used in?
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cholesterol synthesis and fatty acid synthesis
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Why are very strong enzymes needed for the synthesis of NADPH?
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because it exists in large excess. Suitable reactions for its production include aldehyde oxidation and oxidations coupled to decarboxylations
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How does palmitic acid get elongated to form stearic acid?
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2 steps:
1. acetyl CoA to reverse beta oxidation in the mitochondria (elongation here is rare; minor rxn). palmitic acid (16:0) to stearic acid (18:0) 2. The second happens in the ER and uses malonyl CoA and elongase (a multienzyme complex); stearic acid (18:0) to arachadic acid (20:0) |
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How does the stearic acid get desaturated to form oleic acid?
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use the enzyme desaturase in the ER which forms cis double bonds in a specific position of the chain. Animal enzymes tend to form double bonds closer to the carboxyl end.
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Why are linoleic acid and alpha linolenic acid essential FAs for humans?
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essential because mammalian cells are unable to produce double bonds at certain locations
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What is an ex of an essential polyunsaturated FA that is toxic if it is consumed in excess?
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linoleic acid (aka omega-6). The upper limit is 7 g per day to limit the formation of arachadonic acid formation which then converts to eicosanoids that promote inflammation
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What 3 FAs compete for access to delta-6-desaturase?
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oleic acid, linoleic acid, and alpha-linolenic acid
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What kind of omega 6 to Omega 3 ratiodid the hunter-gatherer diet provide and what is the typical american diet?
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Past- equal amounts (.79)
Americans- increased omega 6 and decreased omega 3 (16.74) |
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Why does egg consumption protect against the development of both heart disease and depression?
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contains omega 3 FAs
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How many mg of omega 3 does a regular egg have? Eggland's best egg? egg producer's eggs that use fish meal to feed the chickens?
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37mg
100 mg more than both close to free range chickens, esp DHA and EPA (not ALA) |
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Why do all of animals that Americans currently eat have low levels of omega 3?
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corn fed instead of pasture fed
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What is the single most effective way to prevent heart disease?
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increased consumption of omega 3 FA; healthy individuals should eat fish twice a week and people w/ CHD should consume more (possibly a fish oil supplement). ALso recommended consumption of flaxseed, canola, and soybean oil
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How much omega 3 should be consumed each day for good health?
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omega 6:omega 3 ration
4:1 (SAD- standard American diet is 16:1) 2.5 g/day |
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How much omega 3 should be consumed per day to improve hearing?
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5 g/day
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How much omega 3 should be consumed per day to treat chronic pain?
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7.5 g/day
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How much omega 3 should be consumed per day to treat neurological disease?
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at least 10 g/day
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Why does a high glycemic index diet coupled with high omega 6 FA set Americans up with most diseases that occur with ageing and shorter life spans?
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high glycemic index food and omega 6s are both proinflammatory; also increase risks for heart disease and diabetes
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What tissues synthesize large amounts of triglycerides?
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liver (de novo FA synthesis; DGAT)
gut (FA coming from dietary lipids; DHAP) adipose tissue type 1 muscle cells (slow twitch) mammary glands- of lactating woman |
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What is the rate limiting enzyme for triglyceride synthesis?
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diglyceride acyl transferase (DGAT)
converts diglycerides to triglycerides exception is in the gut (DHAP) |
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List the 6 glycerophospholipids.
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PS- phosphatidylserine
PC- (aka lecithin) phosphotidycholine PE- (aka cephalin) phopsphotidylethanolamine PI- phosphotidylinisitol PG- phosphotidylglycerol DPG- diphosphotidylglycerol |
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How are glycerophospholipids made?
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synthesized in the ER. Necessary to replace mbs w/in the cell. FAs have to be activated by fatty acyl CoA synthase. A source of glycerol-3-P is needed
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What is phosphotidylserine made from?
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CDP-DG + serine or from phosphatidylethanolamine by base exchange using phosphatidyl-ethanolamine-serine transferase
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What is phosphotidylcholine made from?
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CDP-choline + DG or SAM methylation of phosphatidylethanolamine (methyltransferase)
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What is phosphoethanolamine made from?
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CDP-ethanolamine + DG or base exchange with phosphatidylserine
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What is phosphatidylinisitol made from?
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CDP-DG + inositol
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What is phosphatidylglycerol made from?
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CDP-DG + glycerol-3-P
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What is diphosphotidylglycerol made from?
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CDP-DG + PG
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What is essential to form all lipids that have a glycerol backbone?
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phosphatidic acid
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What is the difference between plasmalogens and glycerophospholipids?
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plasmalogens attach FAs to the glycerol backbone with an ether bond instead of an ester bond.
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What is used to form every lipid that has a glycerol backbone?
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phosphatidic acid
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Why did Colleen Lake develop respiratory distress syndrome?
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6 weeks premature causing a deficiency of lung surfactant
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What is surfactant made of?
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dipalmitoylphosphatidylcholine (major component), cholesterol, phosphotidylglycerol, & apoproteins.
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What is the purpose of surfactant?
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to reduce surface tension within the air space, preventing the collapse of the lungs
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When is surfactant formed?
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33 weeks after gestation
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What do drs need to do if a baby is possibly going to be delivered prematurely?
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monitor the baby's surfactant levels by measuring the ratio of lecithin (phosphotidylcholine): sphingomyelin in the amniotic fluid, also by estimating the fetal head circumference by ultrasonagraphy and monitoring for fetal arterial oxygen saturation
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How can a dr speed up the maturity of the lungs?
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by administering corticosteroid 72 hrs before delivery
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What can be added to reduce surface tension if a baby is born with low levels of surfactant? What effect does this have on the baby's mortality rate?
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add synthetic surfactant
no effect on mortality rate |
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What is the ratio of lecithin to sphinomyelin when the lungs are mature and when does this happen after gestation?
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2:1
34 weeks |
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What are the 4 enzymes used for mb lipid remodeling?
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phospholipase A1, phospholipase A2, phospholipase C, & phospholipase D
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What is the relevance of phospholipase A1 in the mb?
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forms lysophospholipids
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What is the relevance of phospholipase A2 in the mb?
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forms lysophospholipids; release FA for eicosanoid synthesis and it is also used to produce lung surfactant
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What is the relevance of phospholipase C in the mb?
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forms diglycerides
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What is the relevance of phospholipase D in the mb?
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forms phosphotidic acid
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Which mb enzyme forms lung surfactant as well as releases FAs for eicosanoid synthesis?
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phospholipase A2
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What does hormone sensitive lipase do?
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cleaves a fatty acids creating DAG from TAG and MAG from DAG
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Where is hormone sensitive lipase found?
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adipose tissue
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What process is hormone sensitive lipase found in?
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lipolysis
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What compounds stimulate receptors?
How do they stimulate receptors? |
epinephrine, norepinephrine, glucagon, ACTH, secretin, and vasopressin
bind to adrenergic plasma mbs and works via an adenylate cyclase, cAMP, and PKA pathway. The PKA activates the enzyme |
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How does ephedrine work?
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stimulates the sympathetic nervous system to get NE released into adipose tissue
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What are the hormone sensitive lipase inhibitors?
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insulin, nicotinic acid, & adenosine
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How does insulin act as an inhibitor on hormone sensitive lipase?
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puts a phosphodiesterase in its active phosphorylated form using PKB to lower cAMP
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How does nicotinic acid act as an inhibitor on hormone sensitive lipase?
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stimulates phosphodiesterase activity to lower cAMP levels; raises levels of inhibitory G protein, and decreases receptor-mediated cAMP formation
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How does adenosine inhibit hormone sensitive lipase?
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inhibits by binding to a receptor that inhibits adenyl cyclase which results in lower cAMP levels
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What are the 2 metabolic classifications that are used for amino acids?
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essential and non-essential
glucogenic and ketogenic |
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What are the 9 essential aas?
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leucine, phenylalanine, valine, methionine, isoleucine, lysine, threonine, histidine, & tryptophan
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What is the daily amount needed and the fxn of leucine?
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1.2 g; branched chain aa that is used for fuel in the brain and muscle
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What is the daily amount necessary for phenylalanine and fxn?
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1.1g; aromatic aa that is used to form tyrosine; competes with tryptophan & tyrosine for transport across the blood brain barrier; high levels induce a serotonin (aspartame use) & dopamine deficit
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What is thought to be the major cause of mental retardation in people with PKU?
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the competition between phenylalanine and tyrosine & tryptophan across the blood-brain barrier
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What is the daily amount needed of valine and fxn?
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1g; branched chain aa used as a fuel in brain & muscle
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What is the daily amount of methionine needed and the function?
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1g; sulfur containing aa used to form cysteine and S-adenosylmethionine (SAM)
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What is the daily amount of isoleucine needed and the function?
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950mg per day. Branched chain amino acid that is used for fuel in brain and muscle
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What is the daily amount of lysine needed and the function?
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800mg; Positively charged (basic) amino acid. Hydroxylated lysine is a major component of collagen and is therefore needed for good wound healing
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What is the daily amount of threonine needed and the function?
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500mg; hydroxylated aa used for O-linked glycosylation and a site for hormone regulated phosphorylation of proteins
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What is the daily amount of histidine needed and the function?
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350 mg; used to form histamine and carnosine; basic aa; carnosine (like taurine) is an approved treatment for congestive heart failure
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What is the daily amount of tryptophan needed and the function?
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250 mg; used to form niacin, serotonin, & melotonin; an aromatic aa
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What are the 5 non-essential aas?
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glutamate, alanine, aspartate, asparagine, and serine
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How is glutamate synthesized?
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precursor= a-KG
enzyme- glu DH or TA |
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How is alanine synthesized?
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precursor- pyruvate
enzyme- TA |
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How is aspartate synthesized?
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precursor- oxaloacetate
enzyme- TA |
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How is asparagine synthesized?
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precursor- aspartate
enzyme- asparagine synthetase |
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How is serine synthesized?
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precursor- 3-phosphoglycerate
enzyme- 3 steps (glycolysis intermediate) |
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What are the 7 conditionally essential aas?
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glutamine, glycine, proline, arg, tyr, cysteine, & taurine
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How is glutamine synthesized? and fxn?
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precursor- glu
enzyme- gln synthetase |
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How is glycine synthesized? and fxn?
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precursor- serine
wound healing |
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How is proline synthesized and whats its function?
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precursor- glu
4steps wound healing |
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How is arginine synthesized and whats its function?
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precursor- glu
urea cycle |
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How is tyr synthesized and whats its function?
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precursor- phenylalanine
enzyme- phe hydroxylase forms hormones and neurotransmitters |
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How is cysteine synthesized and whats its function?
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precursor- methionine
3 steps precursor for glutathione and taurine, antidote for acetaminophen OD, mucolytic agent, used as a nephroprotective agent (against radiocontrast) |
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How is taurine synthesized and what is its function?
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precursor- cyteine
4 steps antioxidant in WBC, stabilize cell mbs in brain/heart, forms bile salts, regulates platelet aggregation, sperm motility |
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How is cholesterol absorbed from the gut lumen and where does that cholesterol come from?
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from bile salts; poorly understood until recently when we discovered that they are emulsified and form micelles are absorbed using a cholesterol transporter (NPC1L1 by passive transport) into enterocytes. Here, free cholesterol is esterified by acyl CoA: cholesterol acyltransferase (ACAT- traps the cholesterol in the cell) and assemble into chylomicrons which are secreted into the lymph and later enter blood.
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How much cholesterol is dumped into the gut everyday?
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2 g
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What pumps cholesterol back into the gut lumen from the enterocytes?
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ATP binding cassette proteins by hydrolyzing ATP
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What competes with the cholesterol transporter?
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plant sterols and stanols
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What is the major ABC protein and what does it do?
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ABCA1; moves cholesterol into HDLs
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What is CE?
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cholesterol ester
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What is C?
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cholesterol
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What does ACAT do molecularly?
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puts oleic acid on cholesterol to trap it into the cell
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How many forms of ACAT are there?
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3
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What is MPT?
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microsomal transfer protein- used to help assemble chylomicrons
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What regulates the amount of cholesterol that is put into chylomicrons?
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ABC proteins
competition w/ plant sterols resin- increase the amount of bile salt lost in feces |
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What is the % of absorbability of dietary cholesterol in humans?
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56% +/- 25%
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What are the 2 different classifications of absorption of dietary cholesterol?
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cholesterol sensitive and cholesterol insensitive
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How does plant sterols and stanols affect the amount of dietary cholesterol that ends up being put into the chylomicrons?
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compete with cholesterol for the cholesterol transporter and for formation of mixed micelles because they are similar structurally. When they are absorbed, they are usually pumped back into the gut lumen
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What happens to LDL-C with age?
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reduces with age; therefore, older people would benefit by foods enriched with plant sterols and stanol esters
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How good are the current NCEP guidelines for LDL in preventing heart attacks?
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LDL not usually different between healthy individuals and those with CAD. HDL is usually too low w/ pts w/ CAD. Needs to be more specific for different types of HDLs & LDLs. small dense LDLs need to be lowered and the HDL2b need to go up.
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What are the emerging risk factors by the NCEP?
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lipoprotein A, homecysteine, prothrombotic factors (fibrinogen), proinflammatory factors (C-reactive protein), and impaired fasting glucose (metabolic syndrome)
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What is the Apo B assay and what does it tell us about the risk of having a heart attack?
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ApoB is a cheap immunoassay that assesses CVD risk. Total number of atherogenic particles more relevant to CVD risk than standard lipid measurements. (although there is no precise correlation)
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What does VLDL, IDL, La(a), and LDL all contain what?
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Apo B
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What lipoprotein in the new lipid profile that was developed at Berkeley provides us with the best estimate of the risk that someone will have a heart attack?
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HDL2b
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What did the Lyon Diet heart study tell us about the role of diet in preventing a second heart attack in people who had already had a heart attack?
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It can help prevent a second heart attack; study showed a 70% reduction in coronary endpoints; AHA low fat diet produced unacceptable higher CVD rates
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What tissues synthesize cholesterol on a regular basis and how much cholesterol gets formed by these tissues in a typical day?
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cholesterol can be synthesized in every cell in the human body except RBCs; 1 g/day most from the liver, skin, testis, ovaries, and the adrenal gland; others don't normally because they get enough from LDL and the gut gets it from the lumen
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WHat is the isopentenyl phosphate pathway and what compounds does this pathway form in plants and animals?
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pathway to form cholesterol also forms bile salts, steroid hormones, vit D, and plant sterols
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What is the rate-limiting step (enzyme along with substrate and product) in the synthesis of cholesterol?
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HMG CoA to mevalonate by HMG CoA reductase
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What is the short term regulation of cholesterol synthesis?
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to phosphorylate the HMG CoA reductase to inactivate it
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How is the HMG CoA reductase phosphorylated?
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this reaction is catalyzed by AMP-dependent protein kinase (aka HMG-CoA reductase kinase) which is active when cellular AMP is high (corresponding to when ATP is low) so that energy will not be expended synthesizing cholesterol
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What is the long term regulation of HMG-CoA reductase?
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Degradation- stimulated by cholesterol, oxidized derivatives of cholesterol, mevalonate, & farnesol (dephosphorylated farnesol pyrophosphate). Enzyme includes a transmembrane sterol-sensing domain that has a role activating degradation of the enzyme via the proteasome
Formation- regulating transcription |
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How is the transcription of HMG-CoA reductase regulated?
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transcription factor SREBP-2 (sterol regulating elements binding protein 2) responds to cellular levels of sterols
sterols are low= SREBP-2 is released by cleavage of a precursor protein found in the ER mbs, a cytosolic domain cleaved from the SREBP precursor protein then translocates into the nucleus where it functions as a transcription factor to activate transcription of genes for HMG-CoA reductase and other enzmes of the pathway of cholesterol synthesis |
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What is cholesterols effect on metabolic regulation of cholesterol synthesis?
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binds to and inhibits HMG-CoA reductase and also inhibits formation of SREBP-2
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What compounds stimulate the degradation of HMG-CoA reductase?
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cholesterol, bile salts, oxidized cholesterol, mevalonic acid, and farnesyl pyrophosphate
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How does insulin regulate cholesterol synthesis?
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stimulates phophoprotein phosphatase and inhibits HMG-CoA reductase kinase to put HMG-CoA reductase in an active dephosphorylated mode
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How does glucagon reguate cholesterol synthesis?
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produces PKA through the cAMP pathway which phosphorylates HMG-CoA reductase kinase (activates it) do deactivate HMG-CoA reductase. PKA also phosphorylates phosphoprotein phosphatase inhibitor 1 (PPI1) which inhibits phosphoprotein phosphatase. This doesn't completely stop cholesterol synthesis.
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When is cholesterol synthesis remain when there is glucagon present?
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formed with glycogen breakdown in the liver and gluconeogenesis in the liver. Also allows cholesterol to be formed in the ketotic state (prolonged fasting state where all liver glycogen is gone)
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What do statins do to cholesterol synthesis?
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competitive inhibitors in the liver; take up LDLs reducing serum levels. Intense doses reduce existing plaques by allowing macrophages to remove existing plaques. decrease inflammation by knocking out key parts of inflammation response, increase serum HDLs; reduce risk for CAD and osteoperosis
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What order do the events of statin take place? Begin with days and end with years.
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LDL-C lowered, endothelial fxn restored, inflammation reduced, ischemic episodes reduced, vulnerable plaques stabilized, cardiac events reduced
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Why are omega 3 FAs so good at preventing a heart attack?
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improve arterial elasticity, anti-inflammatory, increase plaque stability, decrease platelet aggregation, lower Lp(a)
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What is Lp(a)?
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abnormal LDL that is involved in preventing the removal of blood clots; it can only be taken up by macrophages; statins have no effect on it; niacin and omega 3 FA acids lower it
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How much cholesterol is in a typical individual?
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72g
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What 2 tissues have the highest concentrations of cholesterol?
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adrenal glands (100mg/g) and brain (20mg/g) (followed by testis/ovaries(10mg/g), liver(3mg/g), then muscle (1mg/g)
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Where in the cells is most of the cholesterol found?
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membranes
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What are lipid rafts?
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local area of mbs where sphingolipids, cholesterol, and mb proteins are concentrated (cholesterol is critical)
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Why is human milk so high in cholesterol?
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because cholesterol is important in cell signaling, promotes brain growth, and provides the building blocks of hormones, vit d, lipoproteins and intestinal bile
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What is the importance of lipid rafts?
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important in cell signaling
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How much cholesterol does a baby consume a day and what is the daily recommended value for a 150 lb adult?
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1800mg
< 300mg |
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What is the rate-limiting and first enzyme for bile acid synthesis?
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cholesterol-7alpha-hydroxylase
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Where does bile acid synthesis occur?
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ER
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What happens to cholesterol molecule in bile acid synthesis?
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nucleus becomes hydroxylated in 2 or 3 positions and the side chain of cholesterol is shortened and carboxylated resulting in a bile salt
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Where does bile salt synthesis occur?
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liver
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What are the 2 bile salt produced in the liver?
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cholate and chenodeoxycholic acid
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What are some of the physical properties of cholate that differentiate it from cholesterol?
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highly soluble detergent like molecule
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|
What is done with bile acids to make them better detergents?
|
liver puts glycine and taurine with a CoA derivative of the carboxylic acid group. This reaction occurs in the ER. The results are bile salts
|
|
|
Which of the derivatives is found in the highest amounts in bile?
|
glycocholate and glycochenodeoxycholate which are 24% each
|
|
|
What do the gut bacteria do to bile salts?
|
dehydroxylate the primary bile salts into the deoxy forms (secondary bile salts- deoxycholic acid and lithocholic acid) or they can remove the glycine and taurine so that we get taurocholic acid and glycocholic acid (primary bile salts)
Bacteria maked the bile salts less soluble so that they are secreted |
|
|
How much bile salt is secreted into the gut lumen of an avg american eating 3 meals/ day?
|
24g
|
|
|
How much bile salt gets reabsorbed each day?
|
97% gets reabsorbed each day
|
|
|
How does this reabsorption occur?
|
reabsorption occurs in the ileum using the sodium gradient
|
|
|
How can this reabsoprtion be inhibited?
|
reabsorption would be 100% per day if bacteria didn't inhibit reabsorption of some of the molecules by removing the glycine and taurine to form bile acids.
|
|
|
How much of the bile acid in the gut gets reabsorbed?
|
50%
|
|
|
The intake of what food can cause and increased loss of bile salts from the gut?
|
increased intake of fiber
|
|
|
What product of gut bacterial metabolism of dietary fiber inhibits hepatic HMG-CoA reductase?
|
propionate
|
|
|
What are 4 major classes of lipoproteins that are found in human blood?
|
chylomicrons, VLDL, LDL, & HDL
|
|
|
Where do chylomicrons come from and how do they compare to the other lipoproteins?
|
from the intestine; larger than any of the others; composed mostly of triglycerides; filled with food that wasn't soluble
|
|
|
Where do LDLs come from and how do they compare to the other lipoproteins?
|
from the liver from IDLs; mostly made of cholesterol; vit E and other fat soluble antioxidants (Q10 & carotenoids) help to protect LDLs from oxidative damage
|
|
|
Where do HDLs come from?
|
synthesized in both gut and liver
|
|
|
Where do VLDLs come from?
|
liver
|
|
|
WHat is the major protein in HDL and how does this differ from the other 3 major classes of lipoproteins?
|
apo A1; the other are Apo B
|
|
|
What is the major lipid in HDLs and LDLs? What is the major lipid in VLDLs and chylomicrons?
|
CE; TG
|
|
|
List 9 apoproteins that are are found in lipoproteins.
|
Apo AI, Apo AII, Apo B48, Apo B100, Apo CI, Apo CII, Apo CIII, Apo D, and Apo E
|
|
|
What does Apo A1 do?
|
In HDL, binds to the liver SR-B1 scavenger R for HDL uptake by liver, and R on cells needing cholesterol extractions (activates cholesterol efflux from cells via the ABCA1 transporter), activates LCAT (Lecithin- cholesterol acyl transferase) to trap cholesterol in HDL
|
|
|
What does Apo AII do?
|
In HDL, activates hepatic lipase to remove triglycerides from HDL.
|
|
|
What does Apo B48 do?
|
In chylomicrons and chylomicron remnants, binds to the liver LRP (lipoprotein receptor-related protein) receptor, its required for chylomicron assembly and export from the gut. This R also binds estrogen and over 30 other ligands responsible for removing chylomicrons remnants from the blood.
|
|
|
What does Apo B100?
|
In VLDL, IDL & LDL, binds to the LDL R, its required for VLDL assembly and export from the liver
|
|
|
What does Apo CI do?
|
In chylomicrons, VLDL, IDL, & HDL, activates LCAT in HDL.
|
|
|
What does Apo CII do?
|
In chylomicrons, VLDL, IDL, & HDL, activates LPL.
|
|
|
What does Apo CIII do?
|
In chylomicrons, VLDL, IDL, & HDL, inhibits LPL.
|
|
|
What does Apo D do?
|
In HDL, binds LCAT to HDL. Functions as CTEP (cholesterol ester transfer protein) which moves cholesterol from HDL to other lipoproteins as part of reverse cholesterol transport.
|
|
|
What does Apo E do?
|
In VLDL, IDL, HDL, and chylomicrons remnants, binds to the liver Apo B/E LDL receptor to remove IDL, HDL, and chylomicrons remnants from the blood.
|
|
|
What protein is needed for chylomicron formation?
|
Apo B48, Apo CII, & Apo E
|
|
|
What does Apo CII do in chylomicron synthesis?
|
activates lipoprotein lyase which hydrolyzes chylomicrons to free FAs from a core or triacylglyceride
|
|
|
What do muscles do to the free FAs that come from chylomicrons?
|
use them as a fuel
|
|
|
Partially hydrolyzed chylomicrons in the blood stream are depleted of what
|
core of triacyglycerides
|
|
|
How does Apo E help partially hydrolyzed chylomicrons?
|
The R for ApoE are located on liver cells. They help the chylomicrons to be picked up into the liver.
|
|
|
What protein is needed for VLDL formation?
|
both triglycerides and cholesterol esters are in high levels in the core; surface lipids include phosphotidylcholine and unesterfied cholesterol along w/ apo B, C-I, c-II, C-III; mostly importantly 1 apo B per molecule
|
|
|
Where does VLDL synthesis occur?
|
in liver via golgi and ER
|
|
|
How is the synthesis of VLDL increased by dietary regulation?
|
VLDL synthesis is stimulated by increased availability of FAs (esp unsaturated and long chain FAs) and increased FA synthesis (from dietary carbs and alcohol), dietary carbs also increase insuline release which leads to an increase in VLDL production
|
|
|
What do dietary factors not have an effect on in VLDL synthesis and what effect does this have on VLDLs?
|
dietary factors don't increase synthesis of Apo B100 so the main effect is that VLDLs don't increase quantity but size
|
|
|
What does lipoprotein lipase do that effects VLDLs?
|
hydrolyzes triglycerides
|
|
|
What does cholesterol ester transfer protein do that effects VLDLs?
|
transfer additional cholesterol esters from the HDL to VLDL leading to formation of LDL
|
|
|
What proteins are needed for HDL formation?
|
Apo A-1, A-II (liver only), C-I, & C-II
|
|
|
Where does HDL formation occur?
|
plasma from apoproteins formed in the gut and the liver
|
|
|
How does HDL get cholesterol to the liver?
|
Reverse cholesterol transport: uses the HDL to transport CE from extrahepatic tissues to the liver to be eliminated through bile or reincorporated into VLDLs
1. transfer C to cell mbs 2. then to acceptors in extracellular spaces 3. incorporated into HDL 4. Use 1 of 4 types of ABC mb transporters |
|
|
What are the 4 paths of ABC mb transporters used to transfer cholesterol from extrahepatic tissues to the liver
|
ABCA1, ABCG1, HDL R SR-B1 (scavenger receptor B1), and passive diffusion
|
|
|
What is in VLDL besides cholesterol, TG, phospholipids, and proteins?
|
Incorporates many non-soluble things from the liver into VLDL. Including carotenoids, vit E, coenzyme Q10, phytoestrogens, and LDL (VLDL before the triglyceride is removed). Liver also stores vit D and vit K because it uses them.
|
|
|
What tissue removes most of the LDL from the blood?
|
liver (75%) and extrahepatic tissues (25%)
|
|
|
What are the 2 methods of Cholesterol clearance?
|
Receptor-dependent (deficiency leads to hypercholesterolemia) or receptor-independent (poorly understood, possibly due to modifications made in the plasma such as oxidation and glycation)
|
|
|
How much of plasma LDL is cleared daily in normal persons?
|
35%-50%
|
|
|
What pumps phospholipids and cholesterol into nascent HDL?
|
ABCA1
|
|
|
What is LCAT?
|
lecthin cholesterol acyl transferase- moves FA from lecithin (phosphatidylcholine) to cholesterol to form a CE trapping it in HDL; always uses an unsaturated FA and works better with more double bonds on the FA
|
|
|
What is CETP?
|
cholesterol ester transfer protein: moves CE from HDL to chylomicrons or VLDL and picks up a triglyceride in exchange for the CE; engine for reverse cholesterol transport
|
|
|
How do most animals deal with cholesterol?
|
get cholesterol in HDL and then have the liver take up the HDL
|
|
|
How does our cholesterol system differ from that of animals?
|
CETP which causes reverse cholesterol transport
|
|
|
What current drug raises HDL more than any other drug?
|
Niaspin (niacin)
|
|
|
How does Lp(a) or abnormal LDL inhibit the removal of blood clots?
|
inhibits the conversion of plasminogen to plasmin (which cleaves fibrin to degrade clots)
|
|
|
What is Ann Jeina's genetic defect?
|
familial hypercholeterolemia (1/500)
|
|
|
What does familial hypercholeterolemia do?
|
her blood doesn't remove cholesterol as well which leads to the formation of atherosclerotic plaques; increased LDL due to decreased LDL receptors
|
|
|
What are defects that cause hypercholesterolemia?
|
FH and familial defective Apo B100 (1/100)
|
|
|
What class of lipoproteins has the highest atherogenic potential?
|
small dense LDL- associated with rapid uptake into endothelium these are the oxidized ones; w/ more Apo B, more particles can form plaques
|
|
|
What class of lipoproteins has the highest anti-atherogenic potential?
|
Larger HDL2b molecules have the most benefit
|
|
|
What is atherosclerosis?
|
formation of plaques in the wall of major arteries, constricts the lumen of the blood vessel, and decreases the vessel elasticity
|
|
|
What are the risk factors of atherosclerosis?
|
decreased HDL, increased LDL, high total serum cholesterol, infection, inflammation, insulin resistance
|
|
|
How soon is atherosclerosis seen in Americans?
|
Lesions are found as early as 3 years of age
|
|
|
When did heart disease become the number 1 killer in America?
|
1921
|
|
|
When was the AHA founded to fight the new threat of atherosclerosis in America?
|
1924
|
|
|
Who is helped more by our current approach to CVD? and why?
|
men because the current panel doesn't screen Apo A which is the better indicator of heart risk in women?
|
|
|
Why does atherosclerosis occur?
|
inflammatory disease, LDL gets into the intima of the cessel and accumulates, gets easily oxidized. Macrophages eat oxidized LDL and become foam cells forming a fatty streak. Increasing the size of the intima and leads to decreased elastacity of the vessel
|
|
|
What is the driving force of the plaques formed in the bvs?
|
free radical damage and oxidized LDL (which causes inflammation). HDL comes in to take the oxidized LDL out and decrease inflammation
|
|
|
Why do plaques rupture?
|
inflammation in vessels stimulates clot formation leading to the formation of a fibrous cap on the clot. As the plaque begins to build up, it becomes weak and ruptures
|
|
|
What can be used to form stable plaques?
|
statins inhibit HMG-CoA reductase, fish oil is anti-inflammatory increases the uptake of omega-3 FAs.
|
|
|
How can HDL levels be raised through behavioral modifications?
|
exercise, alcohols, smoking cessation
|
|
|
What drugs can raise HDL levels?
|
niacin, fibrates, statins, Apo A 1 milano Apo A1 mimetic, CETP inhibitors
|
|
|
What is a plant toxin (nicotinic acid) useful in preventing CVD?
|
decreases coronary events, increases HDL (esp HDL2b), gets lipoprotein A down and increases HDL2. The only drug to produce a switch from LDL to large buoyant
|
|
|
What are the eicosanoids?
|
most potent regulators of cellular function in nature and are producedby most every cell in the body (except RBCs). They act mainly as "local" hormones affecting the cells that thromboxanes and leukotrienes, lipoxins, HETES
|
|
|
What do eicosanoids do?
|
inflammatory response: destroy mos, repair damage, form blood clots (platelet activation & aggregation)
produce pain, fever, swelling, and exaggerate & inapporpriate expression of normal inflammation (hypersensitivity & allergic rxns) regulate sm contraction increase water and Na secretion (kidneys) regulate bp modulators (can inhibit or stimulate the same process) regulate sleep and wake cycles |
|
|
Where do they come from?
|
eicosanoids derived from polyunsaturated FAs containing 20 carbon atoms
found in cell mbs esterfied to mb phospholipids at the sn-2 position; derived from the diet or synthesized from linoleate |
|
|
What are resolvins?
|
compounds that are made by the human body from the omega 3 FA (eicosapentaenoic acid or EPA); produced by the COX-2 pathway esp in the presence of Aspirin
|
|
|
What do resolvins do?
|
reduce cellular inflammation by inhibiting the production and tranportation of inflammatory cells and inflammatory chemicals to the site
kidney- tool against acute renal failure stabilize plaques |
|
|
Why would COX2 inhibitors interfere w/ resolvin production?
|
COX 2 inhibitors interfere with resolvin production because it is produced in the COX 2 pathway
|
|
|
What 3 enzyme systems are used to produce eicosanoids?
|
cyclo-oxygenase, lipoxygenase, cytochrome P-450
|
|
|
How are FAs released from mb lipids for eicosanoid formation?
|
stimulus interacts w/ specific plasma mb receptors, 2 pathways or enzymes for cleavage upon cell activation (via PLA2 or PLC)
|
|
|
What inhibits PLA2? PLC?
|
steroid anti-inflammatory drugs; not inhibited by steroids
|
|
|
What are the 2 forms of PLA2?
|
intrinsic (production of eicosanoids) and extrinsic (produces lysoglycerophosphoryl-choline, precursor of platelet activating factor- PAF)
|
|
|
How does the PLA2 pathway work?
|
PLA2 specific for sn2 position of phosphoacylglycerol, causes cyt release of arachadonic acid and is the chief enzyme responsible for releasing arachadonic acid for eicosanoid synthesis
|
|
|
How does the PLC pathway work?
|
phospholipase C hydrolyzes the phosphate inositol head group in the mb of the ER generating 1, 2-DAG containing arachidonate. This is cleaved by DAG lipase and Mage lipase
|
|
|
Describe COX1.
|
constitutive (always present) to mediate eicosanoid production as part of homeostasis (vasodilator and vasoconstrictor compounds for local control) (PGH2 synthase=COX1)
|
|
|
Describe COX2.
|
induced by inflammatory mediators and the process of inflammation
|
|
|
How do steroid agents work to control inflammation?
|
block prostoglandin release by inhibiting PLA2 activity and interfering with the release of arachidonate; COX2 inhibition is mediated (control inflammtion by PLA2 but don't inhibit phospholipase C release of arachidonate)
|
|
|
How do nonsteroid agents work to control inflammation?
|
NSAIDS (non-steroidal anti-inflammatory drugs) inhibit cyclooxygenase activity of PGH2 synthase; inhibit formation of prostaglandins in fever, pain, and inflammation; inhibit blood clotting by blocking thromboxane formation by blood platelets
|
|
|
What does aspirin do?
|
acetylates (Ser) a site near the active site of cyclooxygenases (PGH2 synthase) preventing arachidonate binding, blocking production of TXA2 from its major precursor, arachadonate; causes irreversible inhibition platelets because they can't form more enzyme b/c they don't have a nucleus
|
|
|
What does Ibuprofen do to control inflammation?
|
blocks hydrophobic channels by which arachidonate enters the cyclooxygenase active site
|
|
|
What are 2 of the more selective COX2 inhibitors?
|
Vioxx and celebrex
|
|
|
Why are COX2 inhibitors better than COX1?
|
anti-inlammatory and block pain but lack the gastric toxicity that often accompanies chronic use of the less specific NSAIDs that also inhibit COX1
|
|
|
Regular use of either the less specific NSAIDs or COX-II has been shown to decrease the risk of developing ______
|
colorectal cancers
|
|
|
What enzymes are needed to remove prostaglandins from the systemic circulation? and location of these enzymes?
|
15-hydroxy prostoglandin dehydrogenase and prostaglandin reductase (in lungs and kidney)
|
|
|
How do prostaglandins work throughout the body to regulate metabolism?
|
interact with plasma mb G coupled R, the activated G proteins may stimulate or inhibit formation of cAMP, or may activate a phosphotidylinositol signaling pathway leading to intracellular Ca release
regulate gene expression |
|
|
What is PPARgamma?
|
PG R and is related to a family of nuclear R w/ transcription factor activity
|
|
|
What do 15-hydroxy PG dehydrogenase and PG reductase do to inactivate PGs?
|
oxidate C15 hydroxy group that is critical for activity
|
|
|
How are leukotrienes formed?
|
From the linear pathway catalyzed by lipoxygenase
|
|
|
What are leukotrienes involved in?
|
asthma and anaphylactic shock; induce inflammation and asthmatic constriction of the bronchioles
|
|
|
What can be used to decrease leukotriene production?
|
anti-asthma medications, inhibitors of 5-lipoxygenase, drugs that interfere with leukotriene R interactions (singulair and accolate)
|
|
|
Why are life expectancy, infant mortality rate & infant birth defect rates so much worse in the US compared to our peer countries?
|
B/c we don't make use of natural healing or natural inhibitors of inflammation
|
|
|
What are the 5 key components of metabolic syndrome?
|
abd obesity, elevated triglyceride rich lipoproteins (VLDL), reduced HDL, elevated BP, and elevated plasma glucose
|
|
|
Why is the liver a critical tissue in the development of metabolic syndrome?
|
critical in integrating carb and lipid metabolism; has a high perfusion rate; is unable to regulate VLDL formation in metabolic syndrome
|
|
|
What is the prevalence of metabolic syndrome?
|
25%; over the age of 40 more than 40%
|
|
|
What are the risk factors for metabolic syndrome?
|
age, race, obesity, history of: diabetes, hypertension, CVD, polycystic ovary syndrome
|
|
|
What medical conditions are associated with metabolic syndrome?
|
atherosclerosis, cardiovascular disease, type 2 diabetes, fatty liver, non-alcoholic steatohepatitis, sleep apnea, cholesterol gallstones, and polycystic ovarian disease
|
|
|
Why does metabolic syndrome carry such a high risk of having a heart attack?
|
fat on or near the heart increases bp and decreases perfusion; CETP takes cholesterol from fat cells back to the liver (reverse cholesterol transport); low HDLs and high VLDLs; ~50% of people ho have had acute MIs have metabolic syndrome
|
|
|
What is the treatment for metabolic syndrome?
|
Aspirin- decreases risk of heart attack
medication to lower bp (diuretics, ACE inhibitors, Ca channel blockers, & beta blockers) niacin or other medications to regulate cholesterol (reduce LDLs and TGs and increase HDLs) weight loss drugs insulin sensitizers |
|
|
The primary goals of the treatments for metabolic syndrome are?
|
to prevent type 2 diabetes, heart attacks, and strokes
|
|
|
What is the % of effect from drugs alone?
|
7%
|
|
|
What is the % of effect from diet and exercise?
|
8%
|
|
|
What are the % of effect from diet, exercise, and drugs?
|
41% of the time
|
|
|
What are the 4 sources of aa?
|
diet, blood (storage pool), catabolism of tissue proteins, and synthesis in the liver
|
|
|
What role does the liver play in aa metabolism?
|
monitors levels from GI & circulation, 50% of aas entering the liver are catabolized, major site for essential aa catabolism, synthesis of non-essential aa's, oxidation of aa for the urea cycle
|
|
|
Where is the aa storage pool located?
|
blood
|
|
|
What aa's are high in the storage pool?
|
glutamine, ala
|
|
|
What aa's are low in the storage pool?
|
glutamate and aspartate are kept low to protect the brain; methionine is low so protein catabolism would have to occur to sustain high enough levels of methionine for SAM formation
|
|
|
How many grams of proteins are synthesized each day in a typical person?
|
300 g
|
|
|
What is the turnover rate for different kinds of protein?
|
enzymes- 7-10 minutes
protein in liver and plasma ~10 days hemoglobin- 120 days muscle ~180 days collagen ~1000 days |
|
|
Why does protein get broken down and then resynthesized?
|
to prevent accumulatoin of abnormal proteins (errors in protein synthesis and damage to proteins), to allow rapid changes in protein concentration (rate-limiting enzymes), and to have a readily available source of aa's.
|
|
|
What are the 2 ways of getting N out of aa's?
|
transamination reaction and oxidative deamination
|
|
|
What is a transamination reaction?
|
aminotransferases move the amine to alpha-ketogluturate producing glutamate or to oxaloacetate producing aspartate
|
|
|
What is oxidative deamination?
|
removal of amine from glutamate producing an ammonium ion (toxic-possibly b/c it raises blood pH) which will needed to be changed to urea and eliminated
|
|
|
Why is glutamate dehydrogenase such an important enzyme in aa metabolism?
|
reversible rxn, this enzyme releases ammonia in the liver and traps ammonia in extrahepatic tissues and feeds it to the urea cycle (opposite)
|
|
|
In the glucose/alanine pathway, where is glucose synthesized? Where does it go? What is its fate?
|
synthesized in the liver from alanine to pyruvate to glucose
travels in the blood to the muscle tissue In muscle, converted to pyruvate then alanine |
|
|
In the glucose/ Ala pathway? where is ala synthesized? Where does it go? What is its fate?
|
synthesized in the muscle, travels through the blood as a nitrogen source, uptake happens in the liver where it is converted back to glucose or becomes urea
|
|
|
alpha ketogluturate and Alanine with Ala amintransferase=
|
pyruvate and glutamate
|
|
|
glutamate + H2O + NADP with glutamate dehydrogenase
|
alpha ketogluturate + NH3 + NADPH
|
|
|
Where does the amino group removed in the liver go?
|
carbamoyl phosphate
|
|
|
Where is glutamate converted to alpha-ketogluturate?
|
mitochondria
|
|
|
What is AST?
|
aspartate amino transferase
|
|
|
What is ALT?
|
Ala aminotransferase; forms glutamate which goes on to form aspartate which enters the urea cycle in the liver; also better indicator of liver damage
|
|
|
What is the importance of AST, ALT, and alkaline phosphatase?
|
leak into the blood through the mbs of damaged hepatic cells as a result of the inflammatory process; along with bilirubin and B6
|
|
|
Why does total bilirubin increase?
|
result of the inability of the infected liver to conjugate the bilirubin of a partial or a complete occlusion of the hepatic biliary drainage ducts caused by inflammatory swelling in the liver
|
|
|
What happens when B6 is deficient?
|
more ammonia is being produced; pt becomes irritable, insomnia, weakness, nervousness
|
|
|
What are symptoms of excess B6?
|
ammonia toxicity, numbness in feet, arms, & legs, and nerve malfunction
|
|
|
What are the 4 enzymes in the urea cycle?
|
ornithine transcarbamoylase
argininosuccinate synthetase argininosuccinase arginase |
|
|
What are 4 urea cycle intermediates?
|
citrulline
argininosuccinate arginine ornithine |
|
|
What are the 4 major keto acids that are used to accept N in transamination reactions and what aa is formed from each?
|
1. keto-gluturate- glutamate
2. oxaloacetate- aspartate 3. pyruvate- ala 4. glyoxylate- glycine |
|
|
Why are glutamate and aspartate levels kept so low in the blood?
|
to protect the brain due to its status as an NT; they also raise insulin levels and contribute to insulin resistance b/c they stimulate cell R in the pancreas to secrete insulin
|
|
|
What food additives cause problems with glutamate and aspartate?
|
aspartame (artifical sweeteners) and monosodium glutamate (MSGs)
|
|
|
What causes elevations in glutamate and aspartate? And what are the results of this elevation?
|
liver disease causes an increase; causes CNS problems as well as insulin resistance
|
|
|
What can be the consequences of too much MSG?
|
headaches, migraines, stomach upset, tightness in the chest, shortness of breath, heart palpatations, and partial paralysis
|
|
|
What can be the consequences of too much aspartame?
|
alter brain function, behavioral changes, dizziness, headaches, and epileptic-like seizures
|
|
|
What is MSG?
|
sodium salt of the aa glutamate
|
|
|
What is aspartame?
|
phenylalanine linked to aspartic acid
|
|
|
What are the 2 major blood sources of N for the liver formation of urea?
|
glutamine and ala
|
|
|
What is the rate-limiting step in urea synthesis?
|
carbamoyl phosphate synthetase 1 which produces carbamoyl phosphate (not an intermediate in the urea cycle) that feeds into the urea cycle. Occurs in the mitochondria
|
|
|
What 2 enzymes account for about 60% of the total transaminase activity in the body? and what vitamin do they require?
|
AST & ALT; B6
|
|
|
What is the most common vit deficiency detected by cdc?
|
B6
|
|
|
The regulation of carbamoyl phosphate synthetase 1 (CPS-1) is similar to what other enzyme
|
pyruvate DH complex b/c it generates acetyl CoA for TCA
|
|
|
The regulation of CPS-1 is dependent upon
|
N-acetylglutamate
|
|
|
How is CPS-1 regulated?
|
N-acetylglutumate
Arg will speed it up (allosteric activator of N-acetylglutamate synthetase) availability of ammonia or other aa's in the liver conc of intermediates protein in the diet will speed up starvation will slow it down |
|
|
What are the 2 reactions used to trap ammonia?
|
glutamate + ATP + NH4 to ADP + Pi + glutamine using glutamine synthetase (occurs in the mitochondria or cytoplasm of all tissues using 3 isozymes)
glutamine + H2O to glutamate + NH3 with glutaminase (highest activity in the liver, gut, & kidneys to generate ammonia for excretion in the liver; gut-catabolizes all dietary glutamine; brain- NT glutamate) |
|
|
What is phenylacetate?
|
phenyl ketone that is formed in high amounts in patients with PKU
|
|
|
What is phenylacetate clinically used for?
|
given to pts with liver failure to get N out of their bodies. It reacts with glutamine to form phenylacetylglutamine which is excreted
|
|
|
What food additive would increase the production of phenylacetate?
|
aspartame which is broken down into aspartate and phenylalanine. When a person has PKU the phenylalanine is not broken down as usual and the pt is going to get phenylacetate and other abnormal phenylalanine metabolites
|
|
|
What is the problem with PKU?
|
pts lack the enzyme to metabolize Phe correctly, normally it would metabolized to Tyr but instead, it is converted to phenyl pyruvate and then to phenylacetate
|
|
|
What are the uses of glutamine?
|
to form DNA (precursor for purines and pyrimidines), major fuel for rapidly dividing cells (esp immune system, enterocytes, kidney tubule cells, & cancer cells), for formation of glutathione, major substrate for ammoniagenesis (kidney & gut), wound healing, IBD, GI disorders, & peptic ulcers (improves healing of stomach lining)
|
|
|
How much glutamine does the typical diet provide?
|
5-10g/day
|
|
|
When should glutamine be avoided?
|
pts with AIDS/HIV and cancer pts
|
|
|
What is the importance of Arg?
|
intermediate in urea cycle (can be pulled out for other functions), deficiency impairs urea formation, used to make creatinine, glutamate, proline, and glucose, promotes synthesis of NO to relax vessels (atherosclerosis, ED, and intermittent claudation), stimulates release of gastrin, GH, and prolactin, can improve wound healing if Pro is deficient, also used to treat hypertension, migraines, sexual dysfunction in women, and interstitial cystitis
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When should you never give a pt Arg?
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once they have had a heart attack because it agravates the effects of cardiac shock
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How does Viagra fix ED?
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inhibits PDE5 which raises GMP levels and prevents the degradation of NO
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How does Arg help ED and how often does it have to be taken?
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promotes synthesis of NO but 5 g have to be taken everyday
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What should never be combined with large dosages of Arg?
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Viagra
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What is the importance of glycine and proline? what food sources does it come from?
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important part of collagen and therefore important in wound healing; gelatin (from partially digested collagen of animals; 100g contains 13.78 g of gly & 8.9 g of pro)
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Why is gelatin not a complete protein?
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no tryptophan and deficient in isoleucine, threonine, and methionine
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WHat is the importance of tyr?
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used to form hormones and NTs;
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What is tyr formed from?
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phenylalanine using hepatic phenylalanine hydroxylase; poor formation results from ingestion of aspartame by people with poor liver function or PKU
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Too much Tyr can cause:
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arrythmias, racing thoughts, & palpations b/c it is absorbed directly by the stomach
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What is a good source of tyr?
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cheese, esp parmesan cheese (not mozarella)
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What is cysteine and cystine formed from?
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methionine
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What are the 4 aa that contain sulfur?
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cysteine, cystine, methionine, and taurine
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What is cyteine/cystine a precursor for?
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glutathione and taurine
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Why can't cyteine be used as a supplement?
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oxidizes too easily; most dietary comes from cystine or the supplement form N-acetylcyteine which is more resistant to oxidation but has low absorption)
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What is the importance of taurine?
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found in all cells acting as an antioxidant, highest in developing brain (after age 14- in adult brain is replaced by glutamate and excitic NT), used as an inhibitory NT, used to scavenge HOCL, helps stabilize cell mbs to improve retinal photoreceptor activity, CNS neuromodulation, and heart contractability, antioxidant in WBC and detoxifying activity in liver, regulates platelet aggregation, aids in the mvmt of K, Na, Ca, & Mg in & out of the cells, used to form bile salts, improves insulin action, and promotes sperm motility
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What disease is caused by B12 deficiency?
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Pernicious anemia
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What symptoms does pernicious anemia produce?
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tired, weak, smooth bright red tongue, tingling & numbness in hands and feet, shortness of breath, chest pains, heart murmurs, rapid heart rate, heart failure, unsteady mvmt, loss of balance
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How prevalent is this disease?
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1/680 people
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What can cause B12 deficiency?
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lack of gastric intrinsic factor or low stomach acid, total or partial gastroectomy (B12 doesn't disassociate); also impaired absorption in the small intestine
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How can this disease be diagnosed?
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by the schilling test
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If there are normal amounts of cobalamin and normal cobalamin + IF
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dietary insufficiency
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If there are abnormal for cobalamin and normal cobalamin + IF
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intrinsic factor deficiency (gastroectomy, PA)
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Both abnormal cobalamin and cobalamin + IF
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small bowel abnormality (terminal ileum disease)
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What 2 serum metabolites can be measured to access folate and B12 status?
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methylmalonic acid and homocyteine
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Two tests other than the schillings tests that test for pernicious anemia.
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antiintrinsic factor Abs- specific but not sensitive
anti- parietal cell Abs- sensitive but not specific |
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What 2 enzymes require B12 for activity?
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methionine synthetase & methyl malonyl CoA mutase
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What does methionine synthetase do and what form of B12 is required?
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converts homocyteine to methionine using methylated B12
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What does methyl malonyl CoA mutase do and what form of B12 is required for its action?
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methyl malonic acid to succinyl-CoA using adenylated B12
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What happens to homocysteine if there is a deficiency in B12?
folate? |
increase
increase |
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What happens to methyl malonic acid if there is a deficiency in B12?
folate? |
increase
nothing |
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What can happen with a deficiency in B12 with methionine synthetase?
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The folate can enter the "methyl trap"
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The accumulation of methyl malonate due to a deficiency of vit B12 causes what?
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acetyl CoA carboxylase causing neurological disorders due to progressive demyelination of nerve cells; also a competitive inhibitor of malonyl CoA in fatty acid biosynthesis that create branched chain FAs that alter normal mb structure
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What is the methyl folate trap?
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Results when there is a B12 deficiency, results in the inability to remove the methyl group from the B12. The folate can't be used until this is removed
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What level of supplemental folate or animal folate is needed to overcome this methyl-folate trap and prevent the development of anemia in a B12 deficiency?
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1 mg of folate; 50-400 mg are needed per day
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What is the plant and bacterial form of folate?
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polyglutumate which is not absorbed
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How do we process polyglutumate so that we can absorb folate?
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deplutumated and hydrolyzed to form monoglutumate, which is absorbable or entrapped in the food matrix
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What enzyme is used to synthesize the active form of folate?
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folate reductase is used to reduce folate to tetrahydrofolate (THF)
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What drug inhibits folate reductase?
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methotrexate (chemotherapuetic drug)
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What is the form of folate that is produced by the gut for transport in the blood as well as tissue storage?
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methylated to N5-methyl-THF
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How does a folate deficiency lead to elevating serum homocysteine levels?
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folate is needed to eliminate homocyteine, reduces it to methionine
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What dietary factors can increase serum homocyteine levels if they are deficient?
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folate, B12, B6, and choline
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What 2 enzymes and what aa are needed to methylate folate to N5-methyl-THF?
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serine hydroxymethyltransferase (methyl donor), dihydrofolate reductase, and serine
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Why does homocyteine increase the risk of developing heart disease?
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causes increased oxidative stress in the cells that line the arteries, causing increased formation of oxidized LDLs, more foam cells, and more plaques (serum homocyteine isn't part of a standard panel test but is cheap enough to pay for)
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Why does a folate deficiency cause neural tube birth defects?
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folate is needed to help close the neural tube which happens around the 28th day (spina bifida and anencephaly)
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Since the American diet is providing more than the necessary daily intake of folate (fortified grains like flour), why is folate deficiency such a widespread problem?
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caused by dietary deficiency, malabsorption in the small intestine, or drug induced (caused by many drugs including birth control and aspirin)
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What dose of folate should every woman of child bearing age (15-44) take a supplement of each day to prevent neural tube defects?
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400 micrograms
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What dose of folate is needed if she had already had a baby with a neural tube defect?
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4 mg (this dose will mask a B12 deficiency)
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Why is the US not doing a good job and making women get enough folate?
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women are not informed and neither are their doctors
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What 2 compounds are formed using all of the carbons in S-adenosylmethionine?
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polyamines and cyteines
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What kind of compounds get methylated (use only 1 carbon in S-adenosylmethionine) by SAM?
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phenyls, amines, and catecholamines
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What base in DNA gets methylated by S-adenosylmethionine?
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cytosine
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Why is the methylation of DNA important?
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suppresses gene expression
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What are the 5 major fxns of nucleotides?
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building blocks of nucleic acids (DNA & RNA); involved in energy storage, muscle contraction, active transport, maintenance of ion gradients; form activated intermediates in biosynthesis (UDP-glucose, S-adenosylmethionine); components of coenzymes (NAD, NADP, FAD, FMN, & CoA); metabolic regulators (cAMP & cGMP and phosphate donors in signal transduction- ATP, and regulation of some enzymes via adenylation or uridylation)
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What is adenosine?
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a nucleoside, precursor for the nucleotide; controls coronary blood flow or acts as a hormone
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How is adenosine formed?
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from monomeric units of nucleic acid; also a breakdown product of ATP; can be formed in all cells
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What does adenosine do?
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controls coronary blood flow (induces vasodilation), smooth muscle contraction, hormone, neurotransmitter, and induces sleepiness
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What plant chemical blocks adenosines action in the human body?
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caffeine
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How is DNA broken down to form free bases?
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1. DNA to deoxynucleoside 5-monophosphates (nucleotide) via deoxyribonuclease
2. to deoxynucleoside and Pi via 5-nucleotidase 3. to deoxyribose and purines and pyrimidines via nucleosidase |
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What are the 4 sources of the nucleotides that are used to form DNA & RNA?
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1. DNA & RNA from the diet
2. DNA & RNA from cellular turnover 3. de novo synthesis 4. salvaged |
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How is RNA broken down to form free bases?
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1. RNA to nucleoside 5-monophosphates via ribonuclease
2. to nucleoside and Pi via 5 nucleotidase 3. to ribose, purines, and pyrimidines via nucleosidase |
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Which type of RNA turns over the quickest?
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mRNA
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What is PRPP?
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activated form of ribose
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What enzyme forms PRPP?
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R5P pyrophosphokinase
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Where does the substrate for this enzyme come from?
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the substrate (ribose-5-phosphate) comes from the pentose phosphate pathway
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What is PRPP used for?
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used for salvage pathways
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Name the first purine nucleotide and pyrimidine nucleotide formed during the de novo synthesis of nucleotides
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IMP (inosine monophosphate) is the first purine which is a precursor for AMP & GMP
OMP (orotidine -5' monophosphate) first pyrimidine nucleotide formed |
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Name the 5 different compounds that are needed to form the purine ring system.
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glycerine, gluatmine, aspartate, methenyl FH4, & formyl FH4
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Name the rate-limiting enzyme for purine nucleotide synthesis. Regulations?
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amidophosphoribosyl transferase; feed forward stimulation, feedback inhibition
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Three compounds that are needed to form the pyrimidine ring.
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carbamoyl phosphate, glutamate, & aspartate
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What is the rate-limiting enzyme for pyrimidine nucleotide synthesis and regulation?
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carbamoyl phosphate synthetase; PRPP-allosteric binding site & feed forward/back with bicarbonate; inhibited by UMP
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What drugs inhibit xanthine oxidase?
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allopurinol (inhibits the enzyme responsible for converting xanthine to uric acid)
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Why is allopurinol important in treating gout?
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gout is an overproduction of uric acid and therefore this drug inhibits this process
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What are the 2 important end products of pyrimidine base degradation?
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B-aminoisobutyric acid and B-alanine
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Why is B-alanine an important compound?
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reacts with histidine to form carnosine which helps the heart
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What is the end product of purine base degradation?
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Uric acid
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Why is most of the uric acid reabsorbed in the kidney tubule?
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reabsorbed to be further catabolized into allantoin, allantoic acid, urea, ammonia, CO2
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List the 2 nucleotides that are used to form deoxythymidine monophosphate.
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CTP converted to CDP and UMP converted to UDP
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What are the 2 enzymes that are used to convert dUMP to dTMP?
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dihydrofolate reductase and thymidylate synthase
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What is methotrexate?
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a competitive inhibitor- anti-inflammatory, immunosuppressive, antipsoriatic, & antineoplastic
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How does methotrexate work?
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competes with dihydrofolate reductase
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What is 5-fluorouracil, what does it do, and what is it used for?
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a suicide inhibitor- inhibits thymidylate synthase driving the reaction to a dead end complex
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What is leflunomide, what does it do, and what is it used for?
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blocks de novo synthesis of UMP (pyrimidines) by inhibiting dihyrdoorotase; used as a treatment for rheumatoid arthritis and some types of cancers
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What is AZT, what does it do, and what is it used for?
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nucleoside analog (similar to thymidine) that contains an azide group that inhibits reverse transcriptase of the HIV virus
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What is acyclovir, what does it do, and what is it used for?
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nucleoside analog (similar to guanosine) that contains a cyclic sugar group that is used to inhibit the herpes simplex/zoster virus
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Name the enzyme needed to form deoxyribonucleotides.
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ribonucleotide reductase (need thymidylate synthetase to get the thymine before you use the reductase)
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What is thioredoxin and what is it used for?
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a cytoplasmic protein with a large number of sulfhydral groups that function as an antioxidant in deoxyribonucleotide formation (a free radical process); functions in concert with glutathione by generating the free radicals that are necessary for DNA synthesis
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What 7 aa's have a very high turnover rate? (half life of 3 hrs or less)
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tryptophan, ornithine, glutamate, arginine, aspartate, glutamine, & taurine
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How much protein is broken down and then resynthesized in an average person each day?
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300g- 600g
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List the 4 different systems that are used to break down protein in cells.
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ubiquitin-proteasome system, lysosomes, calpains, & caspases
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Describe ubiquitin-proteasome system.
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~80% of total protein breakdown, proteins selected for degradation are conjugated to ubiquitin and then transported to large proteasomes (inhibited by insulin and stimulated by cortisol and IL-1)
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Describe calpains in breakdown of cell proteins.
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Ca2+ activated, initiate degradation of myofibrillar proteins, and inhibited by insulin
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Describe caspases.
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activated by ROS, Ca2+, can cleave actinomyosin and cytoskeletal proteins, and inhibited by insulin
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How does insulin effect the breakdown of proteins in cells?
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stimulates synthesis, released in response to high glucose, suppressed protein degradation by inhibiting ubiquitin-proteasome system, calpains, and caspases, increases aa uptake, and stimulates synthesis, transcription, and translation
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How does cortisol affect the breakdown of protein in the cells?
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stimulates catabolism; released due to stress, increases gluconeogenesis, stimulates ubiquitin-proteasome system with cofactors like exercise, muscle damage, ROS, & Ca2+), and increases proteolysis when cortisol: insulin >4
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What does starvation cause?
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release of cortisol
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What path do SIRS and trauma initiate?
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IL-1 and increase cortisol slightly
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What 3 conditions produce a negative N balance?
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stress, decreased protein intake, and lack of an essential aa
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What 3 conditions produce a positive N balance?
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growth, pregnancy, and recovery
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What test would you order to determine N balance in one of your patients?
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order a 24 hr urine
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When you order a serum prealbumin, what are you trying to find out about your patients?
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reflects acute changes in nutritional status and sensitive indicator of protein status; more sensitive marker due to shorter half life
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Changes in hormone levels are responsible for the metabolic changes that occur during trauma and SIRS. What is responsible for this change in hormone levels? (general term)
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body panics and dumps everything leaving the body with no reserves after the initial shock
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What are the 3 phases that occur in trauma pts?
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Ebb phase (24 hr), catabolic (flow) phase, anabolic (convalescent) phase
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What is happening during the Ebb phase?
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24 hr phase in which metabolic activity is decreased
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What is happening during the catabolic (flow) phase?
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depends on length and severity of the insult, increases the metabolic rate and water and salt retention, all mechanism aim to mobilize nutrients to area of injury (glucose & aa), glycogenlysis & gluconeogenesis leads to increased blood glucose, proteolysis and - N balance lead to muscle wasting, decreased immunity, and organ dysfunction is there is greater than 15% body weight loss, also insulin resistance
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What happens during the anabolic (convalescent) phase?
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up to 4-8 weeks post insult, glycogen & protein synthesis, lipogenesis, and sodium diuresis
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What aa in supplement form is not appropriate for a SIRS pt?
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Arginine- produces massive levels of NO
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What enzymes are needed to remove prostaglandins from the systemic circulation? and their location?
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prostaglandin reductase (removes a double bond) and 15-hydroxyprostaglandin dehydrogenase (converts a hydroxyl to a ketone) ;found in kidney and lungs and convert them to a FA with no hormone capabilities that will later be taken up by the liver
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How do prostaglandins work throughout the body to regulate metabolism?
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bind to plasma mb receptors, acts as a second messenger to change cell metabolism; degraded in the kidney and lungs and then taken up by the liver and subjected to omega-oxidation and beta-oxidation
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