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84 Cards in this Set
- Front
- Back
what is the regulated step in cholesterol synthesis?
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HMG-CoA reductase
(HMG-CoA to Mevalonate, requiring NADPH) |
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what enzyme couples transport of acetyl-CoA with production of NADPH?
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malic enzyme
|
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what are the allosteric inhibitors of HMG-CoA reductase?
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bile acid
cholesterol mevalonate |
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what are the two alternative pathways for cholesterol metabolism to start?
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cytosolic thiolase condensing cytosolic acetyl-CoAs (primary)
mitochondrial acetoacetate from ketogenesis diffusing into cytosol |
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what enzyme converts acetoacetate to acetoacetyl-CoA?
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acetoacetyl-CoA synthase
|
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what is the product of HMG-CoA reductase?
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mevalonate
|
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what is an important intermediate in cholesterol metabolism? what does this intermediate produce?
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farnesyl-PP
prenylated proteins geranylgeranyl-PP heme a and ubiquinone |
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where do statins affect metabolism?
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inhibit HMGR, thus inhibiting cholesterol metabolism
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what are the advantages to statin drugs?
what is the disadvantage to long-term statin therapy? |
A: lowers the amount of cholesterol produced
A: lowers amount of prenylated proteins (many of which are inflammatory proteins) D: decreases heme a and ubiquinone causing muscle weakness and pain |
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what effect does cholesterol have on HMGR? how?
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decreased transcription and translation of HMGR
via SREBP activity |
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what is the short term regulation of HMGR?
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phosphorylation of HMGR via AMPK
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in what way do sterols regulate HMGR?
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ubiquitination, leading to proteosomal degradation, of HMGR
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what enzymes activate AMPK?
how? |
LKB1=STK11=PJK=AMPKK
CaMKK+Ca2+ phosphorylate AMPK |
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what enzyme inhibits AMPK?
how? |
protein phosphatase 2C
dephosphorylates AMPK |
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what enzyme inhibits protein phosphatase 2C?
what is the effect of this? |
PPI-1
inhibition of PP2C decreases inactivation of AMPK, which causes inactivation of HMGR (inhibition of PP2C inhibits cholesterol synthesis) |
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what enzyme inhibits PPI-1?
how? what is the overall effect of inhibition of PPI-1? |
phosphoprotein phosphatase inhibits PPI-1 via dephosphorylation of the enzyme
inhibition of PPI-1 reduces inactivation of HMGR, and reduces inhibition of PP2C, reduced inhibition of PP2C increases inhibition of AMPK, which reduces inactivation of HMGR (overall effect of inhibition of PPI-1 is to stimulate cholesterol synthesis) |
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what effect does cAMP have on HMGR?
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cAMP is the result of glucagon or epinephrine binding, and therefore it causes a decrease in cholesterol synthesis
|
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what is the effect of AMPK on PFK2?
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only acts on cardiac's inducible form of PFK2, increasing its kinase activity, increasing glycolysis
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what is the effect of AMPK on GLUT1 and GLUT4?
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induces their migration to the surface of cells, allowing more glucose into cells
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what is the effect of AMPK on FAS and ACC?
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inhibits FAS and ACC, which activates fatty acid oxidation and inhibits FA synthesis
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what effect does AMPK have on hormone sensitive lipase?
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inhibits, thereby inhibiting lipolysis
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what effect does AMPK have on HMGR?
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inhibits, thereby inhibiting cholesterol synthesis
|
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What effect does AMPK have on GPAT?
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inhibits, thereby inhibiting triglyceride synthesis
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what effect does AMPK have on glycogen synthase?
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inhibits, thereby inhibiting glycogen synthesis
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what effect does AMPK have on eEF2 and mTOR?
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inhibits, thereby inhibiting protein synthesis
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what effect does AMPK have on pancreas?
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inhibits insulin secreation of beta cells
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what effect does AMPK have on the liver?
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inhibits fatty acid synthesis
inhibits cholesterol synthesis |
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what effect does AMPK have on adipose tissue?
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inhibits fatty acid synthesis
inhibits lipolysis |
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what effect does AMPK have on heart?
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increases fatty acid oxidation
increases glucose uptake increases glycolysis |
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what effect does AMPK have on skeletal muscle cells?
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increases fatty acid oxidation
increases glucose uptake |
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which PPAR is the only one which actually proliferates peroxisomes?
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PPARalpha
|
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what type of drug binds to PPARalpha?
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fibrates
|
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what effect does AMPK activation have on SREBP?
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reduces levels, so that cholesterol synthesizing enzymes are not transcribed
|
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what enzyme helps to control intracellular levels of free cholesterol?
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Acyl-cholesterol acyl transferase (ACAT)
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what receptor-mediated uptake mechanism regulates plasma level of cholesterol?
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LDL receptor mediated uptake which delivers cholesterol to the periphery
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what is the reverse cholesterol mediated transport regulated by?
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HDLs which suck cholesterol out of periphery cells and it to liver
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what is forward cholesterol transport?
what is reverse cholesterol transport? |
hepatic to non-hepatic transport of cholesterol
non-hepatic back to hepatic transport of cholesterol |
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what is the role of acyl-cholesterol acyl transferase?
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transfer cholesterol to and from fatty acids, creating and degrading FA esters
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what binding event controls the expression of more than 30 genes in cholesterol synthesis, TAG synthesis, Phospholipid synthesis and FA synthesis?
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binding of SREBP to SRE-1
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what interactions regulate the SCAP protein which controls S1P activity?
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interaction with INSIG
regulation by sterols (high sterol concentration represses SCAP activity) |
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where is SREBP contained until two cleavage events are able to free it?
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ER/Golgi membrane
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what is SCAP?
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SREBP cleavage activator protein
protein which maintains SREBP in ER/Golgi membrane by inhibiting cleavage of two sites by proteases which would release it |
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what two enzymes are responsible for cleaving the two sites on SREBP which allow it to become active?
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Site-1-protease (has to be first for second cleavage site to present)
Site-2-protease |
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how does cholesterol turn off its own synthesis?
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inhibits release of SREBP at SCAP via high concentrations
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what are the two enzymatic effects of statin drugs?
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induce S-nitrosylation of COX-2, increasing production of lipoxins
inhibit HMGR preventing protein prenylation and cholesterol biosynthesis |
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how does nicotinic acid inhibit VLDL secretion?
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suppresses the release of FAs from adipose tissue
(lowers triglycerides and elevates HDLs) |
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what are the problems associated with increasing doses of nicotinic acid?
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liver problems
hyperglycemia gout "flushing" |
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what does nicotinic acid bind to to initiate it's effects on cholesterol metabolism?
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GPCR which causes a signal cascade to reduce amount of FAs released (GRP109A)
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how do fibrates change the amount of serum cholesterol?
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increase beta-oxidation via binding to PPARalpha, decreased TG secretion from liver
increases LPL activity increases level of HDL |
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what effect do cholestyramine related resins have on cholesterol metabolism?
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bind bile acids, causing them to be excreted, which leads to diversion of cholesterol into bile acid synthesis
(also increases synthesis of LDL receptor) |
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where is the only place that conatains ALL of the enzymes for synthesizing bile acids?
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liver
|
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where are bile acids modified?
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intestinal bacteria
|
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when do bile acids change from primary to secondary designations?
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primary - synthesized by liver
secondary - modified by intestines |
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what are the primary bile acids?
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cholic acid
chenodeoxycholic acid |
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what are the secondary bile acids?
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deoxycholate
lithocholate |
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which primary bile acid is the precursor for deoxycholate?
for lithocholate? |
cholic acid -> deoxycholate
chenodeoxycholic acid -> lithocholate |
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what modifications are made to bile acids in the liver, which allow them to stay in aqueous phase (emulsifying fats)?
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addition of glycine and taurine
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what hormone stimulates the peristaltic contractions of the gall bladder, causing it to squeeze bile into the large intestine?
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cholecystokinin (CCK)
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what is involved in the process of enterohepatic circulation?
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liver -> gall bladder -> intestine -> liver
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what are the important functions of bile acids?
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only way to remove cholesterol from body
emulsify dietary lipids to make them accessible to pancreatic lipases facilitate absorption of fat-soluble vitamins prevent precipitation of cholesterol in gallbladder |
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through what mechanisms do bile acids effect expression of numerous genes?
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activation (by binding to) of FXR and PXR
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what is LXR? FXR? PXR?
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Liver X Receptor
Farnesoid X Receptor Pregnane X Receptor (all bind retinoids) |
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what is a xenobiotic?
what tissue is good at removing xenobiotics? |
foreign chemical
liver |
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what step initiates bile acid synthesis?
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7-hydroxylation of cholesterol
|
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what enzyme catalyzes the rate-limiting step in bile acid synthesis?
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7alpha-hydroxylase
(CYP7A1) (requires Oxygen and NADPH) |
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what precursor molecule can be converted to either of the two primary bile acids?
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7-hydroxycholesterol
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what enzyme's transcription is regulated by bile acids' effects on FXR?
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sterol 12alpha-hydroxylase
(CYP8B1) |
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what is the advantage to linking primary and secondary bile acids with glycine or taurine?
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lower pKa values
remain ionized over larger pH range |
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what circulation system returns bile to liver?
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portal circulation
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what inhibits CYP7A1?
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small heterodimer partner (SHP) binding to it
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what transcription factor (with bile acids attached) activate SHP?
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FXR (which needs bile acids bound to be a transcriptional regulator)
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which bile acid is most prominent?
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cholic acid
|
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what enzymes/proteins does FXR repress expression of?
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SREBP
CYP8B1 SLC10A1 (NTCP) |
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why is NTCP necessary in the liver?
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required for uptake of bile acids
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Expression of what proteins/enzymes are induced by FXR?
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SHP
BSEP (ABCB11) MDR3 (multidrug resistant protein) (ABCB4) MRP2 (multidrug resistant related protein) |
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what does BSEP do?
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helps in export of bile salts out of liver into bile canaliculi
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what causes familial intrahepatic cholestasis types 2 and 3?
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BSEP (2)
MDR3 (3) |
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what is cholestasis?
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blockage of bile flow from liver to intestines
|
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what is the receptor for lithocholate and other bile acid precursors?
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PXR
|
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what do Guggul lipids do?
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antagonize FXR
activate PXR activate BSEP expression independent of FXR effectively cause more bile to be exported, which causes conversion of more cholesterol into bile |
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what is HNF-4alpha?
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hepatocyte nuclear factor 4alpha
(not exclusively in hepatocytes) |
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what effect does PXR have on HNF-4alpha?
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inhibits
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what transcription factor does HNF-4alpha function with?
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PGC-1alpha
|
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what does PGC-1alpha activate in bile acid synthesis?
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CYP7A1
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