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106 Cards in this Set
- Front
- Back
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How much of the cardiac output does the liver recieve each minute?
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20-25%
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At what point do portal and hepatic artery blood mix in the liver?
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in the sinusoids
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What is the direction of bile compared to blood flow?
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opposite but parallel
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hepatocytes occupy about 80% of the volume of the liver. what is the percentage of hepatocytes in the parenchyma?
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60%
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What are pit cells and where are they found?
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they are liver specific natural killer cells located in the sinusoidal lining
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What type of capillaries are found in the sinusoids?
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fenestrated
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Can chylomicrons fit through the fenestrations of the sinusoids?
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no, but their remnants can
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Where are kupferr cells located?
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in the sinusoids
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What are some things that kupffer cells remove from circulation?
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old RBC's, denatured albumin, bacteria and immune complexes
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What are other names for stellate cells?
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ito or perisinusoidal cells
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What is the function of stellate cells?
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store lipid and vitamin A, control the turnover of connective tissue and extracellular matrix and regulate contraction of sinusoids
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What cells are primarily responsible for the fibrosis that occurs cirrhosis?
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ito cells
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What cell type in the liver prevents against tumor and virus infected cells?
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pit cells (liver specific natural killer cells)
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What are xenobiotics?
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compounds with no nutrient value and are potentially toxic
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If a lipophilic xenobiotic is taken in what process occurs initially?
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phase I reactions oxidize, hydroxylate, or hydrolyze the compound to make it more soluble
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What is the purpose of phase I reactions?
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to add or expose hydroxyl groups on hydrophobic molecules so that conjugation (phase II reactions) can occur
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Phase II reactions typically add a negatively charged group such as?
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glycine or sulfate
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Where do the compounds used for phase II conjugation come from? Give examples?
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they are synthesized in the liver. For example sulfate can be obtained from cysteine or methionine which are synthesized in the liver
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What are steroid hormones often conjugated with?
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sulfate from cysteine and methionine
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What are the 3 major sites of xenobiotic transformation?
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liver, kidney, intestine
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What enzymes are involved in peroxidation, oxidation, and reduction of exgenous and endogenous substances?
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P450 mono-oxygenase pathway
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What are the two main molecules in the P450 mono-oxygenase pathway?
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NADPH-cytochrome P450 oxidoreductase and cytrochrome P450
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What molecule is the terminal electron acceptor and substrate-binding site of the microsomal mixed-function oxidase complex?
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cytochrome P450
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What process does cytochrome P450 primarily carry out?
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oxidation of substrates
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What enzyme oxidizes ethanol to acetylaldehyde?
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CYP2E1
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How are cytochrome P450 enzymes named? Use CYP2E1
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CYP = cytochrome P450 family
2 = subfamily E = ethanol 1 = specific isoenzyme |
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What is the major cytochrome in the liver and in enterocytes?
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CYP3A4
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What enzyme degrades statins?
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CYP3A4
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What enzyme does grapefruit juice impair?
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CYP3A4
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What would be the effect of someone taking a statin and drinking daily grapefruit juice?
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increased half life of statins in blood from inhibited CYP3A4
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What are common features of the P450 isoenzymes?
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1)oxidize the substrate, reduce oxygen
2)All have a flavin reductase subunit that uses NADPH 3)all are found in sER adn known as microsomal enzymes 4)all bound to lipid portion of membrane 5)all are inducible 6)all generate reactive free radical intermediate |
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What accepts electrons in the P450 enzymes?
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Fe-heme
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vinyl chloride is used in the synthesis of plastics and can cause angiosarcoma in the liver. During its metabolism what happens if phase II reactions are prevented?
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After phase I reactions an epoxide ring forms in the intermediate which reacts with DNA, protein and causes cell damage. If phase II is working the compound is conjugated with glutathione
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What as example of a compound that is made more toxic the P450 pathway?
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Aflatoxin B1 produced by aspergillus flavus grown on peanuts
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What is the mechanism of damage associated with aflatoxin?
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CYP2A1 makes it into a compound that induces a G to T transition in the p53 gene causing cancer. It also forms adducts with lysine making a hepatotoxin
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When is acetaminophen toxic? What pathway makes it toxic?
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at high doses the pathways of glucuronylation and sulfation are overwhelmed and the CYP2E1 enzyme takes over and makes it into NAPQI. NAPQI is toxic because it binds to proteins
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How is acetaminophen excreted safely by the kidneys?
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it is glucuronylated or sulfated
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How can NAPQI be safely excreted?
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when it is conjugated with glutathione and excreted in kidney. Note that this pathway can also be overwhelmed.
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What results in someone that takes alcohol with acetaminophen?
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alcohol induces CYP2E1 expression and as a result metabolizes more the acetaminophen to NAPQI
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What can be given to someone in order to help rid the body of NAPQI?
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N-acetyl cysteine
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When the body is deprived of glucose the liver produces ketone bodies. what organ cannot use ketone bodies?
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liver, they cross blood brain barrier and are a source of energy for brain
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Some cells cannot synthesize nucleotides de novo. How does the liver help?
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it produces nucleotide bases and secretes them into blood
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What does albumin serve as a carrier for?
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hydrophobic compounds like fatty acids, steroids, some amino acids, vitamins and drugs
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What results from cirrhosis when the liver can't metabolize the excess ammonia? What are the symptoms?
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hepatic encephalopathy, marked irritability, tremor, difficulties with coordination and trouble writing, asterixis
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How are sugars connected to protein when they are excreted?
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1) sugars are O-linked at anomeric carbon to OH of threonine and serine.
2) N-glycosyl linkage to asperigine |
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What is an important example of an O-linked sugar? Why is it important
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N-acetylneuraminic acid (NANA) is sialic acid that is a nine carbon sugar linked to circulating proteins. As the proteins age they lose sugar residues and therefore degraded
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What is the function of asialoglycoprotein receptor?
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removal of proteins that have shortened sialic acid by hepatocytes that are degraded in lysosomes
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What is the major function of the pentose phosphate pathway?
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generation of 5 carbon sugars and NADPH, ribose for DNA, RNA, etc...
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What is NADPH important for?
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it is needed in all cell types to regenerate reduced glutathione via the enzyme glutathione reductase and for the cytochrome P450 enzymes
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What amino acid uses NADPH for its synthesis?
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proline
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What is the rate limiting enzyme of the pentose phosphate pathway?
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glucose-6-phosphate dehydrogenase. As much as 30% of glucose is shuttled to this pathway
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Does the liver require oxygen for many of its reactions?
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yes the p450 enzymes use and as a result 20% of total oxygen is used in the liver
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Where are the sugars galactose and fructose primarily metabolized?
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liver
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The GLUT2 transporter has a high Km for glucose. what does this mean in relation to glucose absorption?
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The liver will absorb glucose when the sugar is high like after a meal, but not when the sugar is low ~5mM
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What are the major lipids oxidized in the liver?
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long chain fatty acids like oleic, stearic, palmitic acid
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What types of fatty acids are found in adipose tissue and meat and dairy predominately?
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long chin fatty acids
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What organs can degrade medium chain fatty acids?
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liver and the kidney somewhat
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What type of fatty acid is found in a mothers milk?
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medium chain fatty acids
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Which type of fatty acid is more readily hydrolyzed from a TAG by pancreatic and gastric lipase?
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medium chain fatty acids
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What type of fatty acid is released directly into portal circulation?
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medium chain fatty acids
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What size fatty acids are water soluble?
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C8 chains and less
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WHat is the chain length range for long, medium and short chain fatty acids?
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long-C20 to C12
medium C12 to C4 short C4-C2 |
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How are medium chain fatty acids taken into mitochondria? What enzyme is responsible for their activation to acyl-CoA derivatives?
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1)diffusion
2) medium chain length fatty acid-activating enzyme (MMFAE) Note: the medium chain acyl CoA is then oxidized by the normal route beginning with medium chain length acyl CoA dehydrogenase |
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What type of fatty acids are peroxisomes needed for?
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very long chain fatty acids such as C24:0 and phytanic acid
Note: they are also needed for cleavage of cholesterol side chain to make bile and biosynthesis of ether lipids |
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What enzyme do peroxisomes have to deal with oxygen radicals?
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catalase
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What activating enzyme is present in the peroxisome membrane that makes acyl CoA derivatives of very long chain fatty acids?
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very long chain acyl CoA synthetase
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After very long chain fatty acids are activated with acyl CoA what happens?
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The activated derivatives are oxidized by liver peroxisomes to the octanoyl CoA level.
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People that are hospitalized with GI problems such as pancreatic insufficiency, cholestatic liver disease, ileal disease or resection should receive what type of fatty acid to avoid being malnourished?
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medium chain length fatty acids
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What could be a problem with long term diet consisting only of medium chain triglyercerides?
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MCT cannot be used as percursors for eicosanoids
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What is the difference between mitochondrial and peroxisomal beta oxidation?
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in the peroxisome the first enzyme introduces a double bond and generates hydrogen perodixe instead of FADH2. The remainder of cycle is same
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What can the acetyl CoA made by the peroxisome be used to synthesize?
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cholesterol and dolichol
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What is Zellweger syndrome? What results in this disease?
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also called cerebrohepatorenal syndrome is the absence of peroxisomes in all tissues. Patients accumlate C26-C38 polyenoic acids in brain tissue becuase of defective peroxisomal of VLCFA synthesized in the brain for myelin formation. Bile and ether lipid formation are impaired in liver
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What are agonists of the PPARs?
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hypolipidemic agents, NSAIDS, environmental toxins
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What results when PPARs are stimulated?
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They are nuclear receptors that stimulate transcription of gene that are involved in beta and omega oxidation of fatty acids
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What are the 3 type of PPAR receptors? When the fatty acid concentration increases in the blood which PPAR is increased?
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1) alpha, delta/beta, gamma
2) alpha in liver so when fatty acids hi alpha increases |
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Would a deficiency in the alpha PPAR be expected to be worse for someone in the fasting or overfed state?
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Both lead to fatty liver. There is an inability to increase beta oxidation and inability to make glucose and ketone bodies. With a normal diet nothing abnormal results
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What are examples of xenobiotics that are detoxified using fatty acid metabolism pathway?
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hydrophobic compounds
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What preservative found in plants and added to cola is metabolized with beta oxidation pathway?
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benzoate
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What enzyme activates the xenobiotics salicylate and benzoate? What is conjugated with the activated intermediates?
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MMFAE makes an acyl CoA derivative. Conjugated with glycine to make salicylurate and hippuric acid
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If someone has hyperammonemia what can be given?
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benzoate because its metabolite hippurate is excreted in the urine it can lower the free ammonia pool
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What is the purpose of giving someone fibrates?
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given to people with elevated triglycerides to increase the peroxisome concentration and decrease serum lipids
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What fibrates suppress and increase in addition to peroxisomes?
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suppress ApoCIII and increase LPL. ApoCIII normally inhibits LPL and blocks apoE on IDL particles causing IDL to accumlate in serum.
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What is an example of a fibrate?
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clofibrate
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What is the function of lethicin cholesterol acyltransferase (LCAT)?
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transfer of a fatty acid from the 2-position of lecithin to the 3beta-OH of free cholesterol.
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Where is LCAT located?
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in the serum
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What results in liver disease as far as cholesterol in blood?
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The level of cholesterol ester and lysolecithin decrease and free cholesterol levels increase
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What serum enzymes besides LCAT are reduced in liver disease? what results?
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LPL and hepatic triglyceride lipase.
accumulation of plasma triglycerols |
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What is the difference in LDL composition in someone with LCAT dificiency compared to someone with normal LCAT?
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LDL in LCAT deficient people is triglycerol rich and has decreased cholesterol-ester
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A patient with vomiting, and progressive CNS damage, and hypoglycemia may have what condition?
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Reyes syndrome in which there is mitochondrial dysfunction with decreased activity of hepatic mitochondrial enzymes. Hepatic coma can occur because of increased ammonia
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What is Reye's syndrome associated with?
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aspirin overdose, but there are other conditions... of course none them are mentioned
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How does LCAT affect HDL2 and HDL3?
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LCAT converts HDL3 to HDL2. HDL2 removes most of the cholesterol.
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Why does atherosclerosis occur when LCAT is deficient?
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there is more free unesterified cholesterol in blood
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Is HDL3 or HDL2 more antiatherosclerotic?
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HDL2
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In cirrhosis the level HDL2:HDL3 is elevated. How is this possible given that LCAT is deficient?
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HDL2 is converted by LPL to HDL3. Even though LCAT is deficient so is LPL and LPL is the more dominant of the two mechanisms
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In cirrhosis how are VLDL, LDL, NEFA changed?
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VLDL is decreased
LDL is normal (reason not known) NEFA are elevated because glucose output is low in these patients so they compensate by having high levels of NEFA for energy |
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In an adult what can be said about the total protein content?
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It is constant as compared to a growing child. Therefore the rate of amino acid degradation and intake are about equal
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What amino acids are used as fuel in the gut as fuel after a high protein meal?
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aspartate, glutamate, glutamine
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During fasting what amino acid is primarily used by the gut?
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glutamine
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How is the nitrogen from certain amino acids passed to the liver from the gut?
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as citrulline or ammonium ion via portal blood
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What type of amino acids predominately bypass the liver and go to other tissues for energy and protein synthesis?
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branched chain amino acids, such as leucine, isoleucine and valine. These are essential amino acids
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How is amino acid nitrogen disposed of by skeletal muscle, kidney and intestinal mucosa using the pyruvate-glucose-alanine cycle?
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nitrogen is added to alanine which is released into the blood to go to liver
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How is amino acid nitrogen disposed of by skeletal muscle, lungs and neural tissues?
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muscle: alanine, glutamine
lung and neural tissues: glutamine |
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What organ disposes of amino acid nitrogen by releasing serine into the blood?
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kidney
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in someone with liver disease what would you expect the amino acid concentration in the blood to be?
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increased
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If an amino acid profile of a diseased liver patient were determined what would the results show?
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increased aromatic amino acids (tryptophan, phenylalanine and tyrosine) These may be increased from decreased liver utilization of portal blood
decreased BCAA |
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Would someone with an amebic infection of the liver or alcoholic liver have micronodular cirrhosis?
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alcoholic liver has regenerative nodules that appear.
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