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68 Cards in this Set
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- Back
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Arachidonic acid
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20:4w6
Found in plasma membrane, "stored" in membrane phospholipids; cleaved out by PLA; converted either by cyclooxygenase or lipoxygenase and cell-specific synthases to other end-products |
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Eicosanoids
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Derivatives of arachidonic acid
Short-lived "local" hormones (autocrine or paracrine) Found in all tissues Involved in gastric maintenance, platelet aggregation, vasoconstriction or dilation, smooth muscle contraction or relaxation, inflammation, fever, and allergic response Types include: prostaglandins, thromboxanes, and leukotrienes |
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Prostaglandins
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Vasodilation
Inhibition of platelet aggregation |
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Thromboxanes
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Vasoconstriction
Promotion of platelet aggregation |
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Leukotrienes
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Promote vascular permeability (edema of inflammation) and are bronchoconstrictors (mediators of allergic response)
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Anti-asthmatic drugs
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Anti-asthmatics inhibit leukotriene synthesis
or Leukotriene receptor antagonists Get relaxation of bronchi |
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Phospholipase A2
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Releases arachidonic acid precursor from phospholipids in cell membrane
Inhibited by SAIDs |
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Cyclooxygenase
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COX-1 and COX-2, for example
Convert arachidonic acid precursor into a precursor that is destined to become prostaglandin or thromboxane |
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Lipoxygenase
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Enzyme that converts arachidonic acid into leukotrienes
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SAIDS
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Steroidal Anti-Inflammatory Drugs
Inhibit PLA2, preventing release of arachidonic acid Don't get lipoxygenase or cyclooxygenase activity Ex. hydrocortisone |
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NSAIDs
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Non-steroidal anti-inflammatory drugs
Inhibit cyclooxygenases (COX 1 and/or COX 2) Have pros and cons; COX1 protects stomach lining and COX2 has anti-heart attack effects Include: aspirin (irreversible inhibition), acetaminophen (Tylenol- not a strong anti-inflammatory), ibuprofen (Advil, Motrin - anti-inflammatory), naproxen (Aleve) |
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COX-2 inhibitors
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Eg. Vioxx, Celebrex, Meloxicam, Bextra
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Aspirin
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Irreversibly inhibits cyclooxygenase
Requires new protein synthesis for recovery of prostaglandin activity Other COX1/2 inhibitors are reversible |
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Bile salts
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Hydrophobic and hydrophilic surface = amphipathic
Made from cholesterol in the liver and stored in the gall bladder Secreted into gut after a meal Form mixed micelles with dietary fats that allow attack by water-soluble enzymes (lipases) Provide transport vehicles for less-soluble lipids (cholesterol and fat-soluble vitamins ADEK) |
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Pancreatic lipase
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Hydrolyzes dietary fats to free fatty acids and monoacylglycerols
Bile salts emulsify, and pancreatic lipase frees up FA and MAGs in intestinal lumen |
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Medium chain fatty acids
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Less than or equal to 12 C
Absorbed directly into portal circulation |
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Longer chain fatty acids
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Greater than 12 C
Converted back to TGs in intestinal mucosal cells Incorporated into chylomicrons Enter lymphatic system, then blood |
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Chylomicrons
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Globs of dietary TG + cholesterol + phospholipids
Transport of longer chain fatty acids that have been broken down from dietary fats Leaves gut, enters lymphatic system, then blood; adipose for storage, muscle for energy |
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Lipid metabolism: Fed State
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Insulin present
Dietary TG emulsified by bile salts and hydrolyzed to FFA and MAG in intestine by pancreatic lipase TG resynthesized in mucosal cells and exported to lymph as chylomicrons TGs cleared from chylomicrons by lipoprotein lipase FFAs released can be used as energy by exercising muscle, converted to fat by adipose tissue, or converted to TG and exported as VLDL by liver (remodeling) TG also cleared from VLDL by lipoprotein lipase Excess glucose and AAs also converted to TGs |
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Lipoprotein lipase
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Clears TGs from chylomicrons as enters fat, muscle or liver
Also clears TGs from VLDL from liver |
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VLDL
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Very low-density lipoprotein
Fatty acids that have been remodeled from dietary fats in liver are carried to other tissues as VLDL Lipoprotein lipase clears TGs from VLDL |
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Lipid metabolism: Fasting state
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Glycogen breakdown in liver and protein breakdown in muscle coupled with gluconeogenesis in liver provide blood glc for brain and RBCs
Glucagon (fasting) and epinephrine (exercise) stimulate HSL in adipose tissue; used for energy by most tissues except brain and RBCs (fat, muscle, liver) Glycerol released by adipose tiss can be converted to glucose by liver (minor) Acetyl-coA from FFA degradation in liver can be converted to ketone bodies during starvation |
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HSL
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Hormone sensitive lipase
Stimulates breakdown of TGs to FFA for use by adipose tissue and release to blood for liver and muscle |
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Insulin: lipid metabolism
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Inhibits HSL (HSL acts in fasting state)- no FFA released from adipose
Stimulates glycolysis; some acetyl-coA used to generate E, most converted to fat Stimulates FA and TG synthesis Stimulates lipoprotein lipase (frees TG from VLDL for storage in adipose and from chylomicrons to be converted to FA in liver) |
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Fed state: resting muscle
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Insulin:
+ GLUT 4 (glucose uptake) + Glycogen synthesis (glycogen synthase) + Protein synthesis Glycolysis driven by mass action |
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Fasting and starvation: adipose and liver
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Adipose:
Glucagon: +HSL, +TG breakdown FFA released to blood Liver: FFA converted to Ac-coA; combines with OAA for energy Glucagon: (+)gluconeogenesis (OAA to glucose); (-)TG synthesis As gluconeogenesis depletes OAA levels, acteyl-coA can't enter CAC and ketogenesis increases |
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Fasting and starvation: resting muscle
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No glucagon effect; insulin not produced
No glucose taken up, fatty acids are primary energy source Protein synth not stimulated --> proteolysis and release of AAs (for gluconeogenesis) |
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Type 1 diabetes: general
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Insulin is not produced
HSL increases (insulin normally negatively regulates) and FFAs accumulate FFAs drive beta-oxidation in liver Acetyl-coA accumulates FA/TG synthesis decreases Gluconeogenesis increases and acetyl-coA converted to ketone bodies Net result = hyperglycemia and ketonemia |
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Type 1 diabetes: resting muscle
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Protein synth not stimulated --> proteolysis and relase of AAs for gluconeogenesis
No glycogen synthesis (no insulin signal) No glucose uptake via GLUT4 transporter (no insulin signal) High blood glucose, basal uptake via GLUT 1 and GLUT 3 Glycogen stores not severely depleted |
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Type 2 diabetes: resting muscle
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Muscle is insulin resistant, but because insulin is overproduced, can still operate reasonable well
High concentration of FA drives TG synthesis and accumulation in muscle Pyruvate accumulates faster than it can be used for energy, so increased lactate production So, hyperuricemia and decreased incidence of ketosis |
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Type 2 diabetes: liver
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Tissues insulin resistant, but insulin overproduced
Gluconeogenesis increases (not as much as in type I) Adipokines (e.g. TNFalpha) stimulate HSL causing release of FFA by adipose Mass action--> fatty acid accumulation in liver Beta oxidation is inhibited TG accumulation in liver Lactate in blood produces both OAA and acetyl-coA so that can do CAC (so no ketone bodies) Fatty acid and TG synthesis are stimulated Excess TGs exported as VLDL Adipokines inhibit LPL So dyslipidemia (TG rich VLDL) and hyperglycemia |
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Source of all carbons
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Acetyl-coA
Get acetyl-coA from proteins --> alanine --> pyruvate Glucose --> pyruvate CAC --> OAA --> PEP --> pyruvate (gluconeogenesis) |
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Biosynthesis FA: overview
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Acetyl-coA + NADPH + ADP required
Occurs in cytosol |
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Acteyl-coA: cross mit mem?
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Citrate & pyruvate shuttle
NADPH is generated in cytosol; consumption of NADH so glycolysis can continue at max rate |
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Key enzymes of FA synth
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Acetyl-coA Carboxylase
Fatty acid synthase |
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Acetyl-coA carboxylase and isozymes
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Converts acetyl-coA to malonyl coA "activated intermediate"
Rate limiting step, tightly regulated Requires biotin (adding CO2) and ATP Isozymes: ACC-1: liver and adipose cytosol ACC-2: mitochondrial membrane of muscle and liver (malonyl-coA for inhibition of b-oxidation in fed state by inhibiting movement of FA into mitochon) |
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Fatty acid synthase
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Catalyzes remaining reactions of FA synthesis (besides acetyl-coA --> malonyl-coA)
Has group similar to coenzymeA from pantothenic acid (both are high E thioester bonds) |
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FA biosynthesis: pathway
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Acetyl-coA + malonyl-coA --> condensation (ketone) --> reduction (alcohol) --> dehydration (2x bond) --> reduction (fully reduced, + 2 C)
Gets longer on methyl end with carboxylic acid on other end 7 cycles of adding 2C --> palmytic acid (16 C) Thiolase cleaves FA from fatty acid synthase |
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Palmytic acid
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16C product of FA synthesis (7 cycles)
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Remodeling
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Fatty acid modification
Desaturases (require copper) Elongases *We lack enzymes to introduce 2x bonds in the w6 and w3 positions --> must EAT them |
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Regulation FA synthesis: cellular, whole body
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Occurs at acetyl-coA carboxylase step
Citrate activates, palmitoyl-coA inactivates (end product) Whole body: Insulin stimulates, glucagon inhibits PHOSPHORYLATION of the carboxylase INHIBITS it; DEPHOSPHORYLATION ACTIVATES |
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Palmitoyl-coA
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Inhibits FA synthesis (end product)
Binds to allosteric site on acetyl-coA carboxylase, decreasing its activity (partial inactivation) |
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Citrate regulation FA synthesis
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Citrate binds allosteric site on carboxylase and partially activates
May be partial explanation for TG overproduction associated with Type II diabetes (CAC stimulated by lactate buildup) |
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AMP-PK
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Regulator of FA synthesis
Turns off acetyl-coA carboxylase (phosphorylates) during fasting and exercise; allows b-ox for energy Active when AMP is high (fasting and exercise); inactive when glucose is high (fed state, type II diabetes) |
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SREBP
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Sits on enhancer, turns on synth of mRNA for acetyl-coA carboxylase, FA synthase, and gly-3-P acyltransferase
Originally in ER; moves to nucleus via golgi and protease modification Stim by insulin and adipokines (TNF-like) Inhibited by PPARa (PUFA, fibrate drugs turn on PPARa) |
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PPARa
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TF that inhibits maturation of SREBP getting into the nucleus
Stim by PUFA (omega-3 FA) and fibrate drugs Up-regulates B-oxidation |
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PPAR-gamma
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Controls adipocyte differentiation
Controls insulin sensitivity |
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Chronic high glucose...
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Increases ACC activity
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Triglyceride synthesis
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Liver generates glycerol from glycerol kinase; adipose and fat must make their own
Phospholipids made in fed or fasting state (phosphatidic acid, all cells) Enzyme: glycerol-3-P acyltransferase Turned on in fed state and inappropriately in |
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Key enzyme of TG synthesis
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Glycerol-3-P acyltransferase
Turned on by insulin and TNF-alpha adipokines that turns on SREBP-1 enhancement Turned off by PPAR-a (PUFA, fibrate drugs) that turns of SREBP-1 enhancement |
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HSL: hormones
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Hormone sensitive lipase
Glucagon and epinephrine activate Insulin inhibits |
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FFA are transported through the bloodstream...
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bound to albumin
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Transport FA into mitochondria
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Transported as acyl carnitine
Carnitine palmitoyltransferase-I (CPT-1): rate lim Endurance exercise incr CPT-I levels CPT-II also important |
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Activation FFA
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Once inside cell
Acyl-coA synthetase |
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B-ox pathway
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Chemically the reverse of biosynth, but different enzymes, occurs in mitochondria, and produces FADH2 and NADH
Each cycle: acytl-coA + what started with(-2C); 5 ATP via FADH2 and NADH One less cycle than 1/2 the number of carbons |
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Peroxisomes in B-ox
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Most efficient with chain lengths greater than C16
Cleaves to C8 and acetyl-coA Other pathways for branched chains and odd chains and unsat. FA |
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Insulin and B-ox
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Malonyl-coA made by acetyl-coA carboxylase inhibits CPT-I, keeping FA from the mitochondria (inhibits b-ox)
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Glucagon and B-ox
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Fasting, glucagon turns on this pathway
Activation of HSL; palmitoyl-coA and glucagon inhibit acetyl-coA carboxylase Like glucagon, acetyl-coA carboxylase is "off" in the phosphorylated form |
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PPAR-alpha
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TF: increases b-ox enzyme levels (CPT-I)
Turned on by w3 PUFAs, exercise, and fibrate drugs Turned off by insulin or glucose; SREBP-1 on in presence of insulin and glc |
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PCG-1
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Stimulates mitochondrial biogenesis
Regular exercise increases the number of mitochondria (more b-ox) PCG-1 and PPAR-alpha have same outcome; PCG-1 inhibits SREBP-1 Glucose decreases PCG-1 to increase FA synthesis |
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Ketone body formation occurs exclusively...
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In liver mitochondria
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Key enzymes of ketone body formation
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1. HMG-CoA synthase
2. HMG-coA lyase Present at high levels in liver mitochondria |
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Utilization of ketone bodies
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Requires transferase found in mitochondria of all tissues except liver
Most tissues use during prolonged fasting Thiolase enzyme low in brain but is induced by starvation for brain utilization of ketone bodies |
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Ketogenesis turned on by...
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Fasting
Type I diabetes "Perceived" increase in glucagon:insulin (type II diabetes) |
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Ketogenic pathway
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HSL activated
B-oxidation Acetyl-coA piles up and is shunted into ketogenic pathway: OAA pulled out of CAC for gluconeogenesis (increase in glucagon) More ketone body formation |
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Type II Diabetes and Ketogenesis
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HSL (for ketogenesis) and ACC (for biosynthesis of FA) are active simultaneously
Lactate provides OAA Citrate and adipokines stimulate ACC Don't get ketosis because have both OAA and acetyl-coA from pyruvate --> CAC Hyperglycemia and increased FA in blood, but not ketosis |
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CPT-I, CPT-II, translocase deficiency
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Hypoketonic (can't get into mitochondria)
Hypoglycemic (depending completely on glucose) Can't do B-ox because can't get into mitochondria CPT-II less severe |
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MCAD defect
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Medium chain acyl-coA DH
Pile up of FAs tie up carnitine and acetyl-coA Prevents b-ox of all FA |
