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Flashcards in Cholesterol Metabolism Deck (19)
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describe the influx and efflux of cholesterol in the liver


describe cholesterol synthesis overview

  • synthesis of cholesterol requires cytosolic acetyl CoA, NADPH and ATP (just like FA synthesis)
  • the rate limiting enzme is HMG CoA reductase
  • occurs in the cytoplasm with enzymes in cytosol and ER


name the sources of NADPH for cholesterol synthesis

similar to FA synthesis

  • PPP
  • Malic enzyme


name the 5 basic steps of cholesterol synthesis

  1. synthesis of HMG-CoA
  2. synthesis of 6-C mevalonate
  3. formation of a 5-C isopentenyl pyrophosphate
  4. condensation of isoprenes to form squalene (C30)
  5. cyclization of squalene to lanosterol followed by cholesterol (C27) formation


describe the synthesis of HMG-CoA

  • involves 3 molecules of acetyl-CoA, 2 NADPH and the energy contained in the thiol ester bonds
  • thiolase catalyzes the linkage of 2 acetyl-CoA molecules to produce acetoacetyl-CoA
  • HMG-CoA synthase catalyzes the linkage of a 3rd acetyl-CoA
    • this produces HMG-CoA (6C compound)


describe the synthesis of mevalonate

  • HMG CoA is reduced to mevalonate
    • reaction is catalyzed by HMG-CoA reductase, the RLE of cholesterol synthesis
    • this is the primary regulatory step of chol. biosynthesis
  • requires 2 NADPH


describe the synthesis of cholesterol from mevalonate

  • mevalonic acid --> 5-pyrophosphomevalonate (requires 2 ATP)
  • 5-pyrophosphomevalonate --> isopentenyl pyrophosphate (IPP, 5C) uses 1 ATP
  • IPP isomerized to 3,3-dimethylallyl pyrophosphate (DPP)


describe how IPP gets to squalene

  • IPP and DPP are linked to form geranyl pyrophosphate (GPP)
  • a second IPP is added to form farnesyl pyrophosphate (FPP)
  • 2 FPPs are linked to form squalene (30C). In the process, pyrophosphate is released, and NADPH serves as a reducing equivalent 


describe how squalene -------> cholesterol

  • squalene is cyclized with NADPH and O2 to form lanosterol via squalene monooxygenase
    • these compounds and the downstream intermediates to cholesterol are so hydrophobic they require carrier proteins to keep them soluble 
  • lanosterol (30C) is converted to cholesterol (27C) by a series of rxns performed in the ER 
    • requires NADPH 


describe the importance of geranyl-groups, farnesyl groups and FPP

  • geranyl groups: used to anchor proteins in the cell membrane
  • farnesyl-groups: needed in specific proteins
  • Farnesyl-PP (FPP): branches out for the synthesis of:
    • CoQ of the ETC 
    • Dolichol-PP needed for N-glycosylation of proteins


describe cause of Smith-Lemli-Optiz Syndrome (SLOS)

  • deficiency of 7-dehydrocholesterol reductase
    • responsible for the final step in the production of cholesterol for the correct double bond formation in ring B
  • Loss of function mutation in DHCR7 gene


name clinical signs of SLOS

  • autosomal recessive disorder
  • heart defects, malformation of limbs, growth retardation, microcephaly
  • cholesterol administration helps with growth but not CNS defects due to embryonic microcephaly


describe the degradation of cholesterol

  • the ring structure of cholesterol cannot be metabolized to CO2 and H2O in humans
  • cholesterol metabolized by:
    • conversion to bile acids
    • may be reduced by intestinal microorganisms to corprostanol and cholestanol which are found in feces


name the 2 most abundant organic components of bile

  • phosphatidylcholine (lecithin) and bile salts are most abundant organic components of bile
  • also contains cholesterol, bilirubin


describe the synthesis of bile acids

  • 1st step catalyzed by cholesterol 7alpha-hydroxylase (P450) to form 7-alpha-hydroxycholesterol
    • requires NADPH and O2
    • rate limiting step
    • activated by high cytosolic cholesterol 
    • inhibited by high cholic acid
  • products are cholic acid or chenodenoxycholic acid


describe conjugated bile salts

  • conjugated with -glycine or -taurineb
    • bile salts like glycocholic acid or taurochenodeoxycholic acid are much more effective at solubilizing lipids than bile acids


describe the aciton of intestinal flora on bile salts

  • intestinal bacteria can remove taurine or glycine from bile salts
  • other intestinal bacteria can convert primary bile salts into secondary bile salts by removing hydroxyl groups


describe the enterohepatic circulation of bile salts

  • primary bile salts are metabolized by intestinal bacteria producing secondary bile acids
    • involves deconjugation and dehydroxylation
  • secondary bile acids are reabsorbed by the liver, reconjugated but not rehydroxylated and also become component of bile


describe cholesterol gallstone disease (cholelithiasis)

  • precipitation of cholesterol (in bile) in the gallbladder due to deficiency of lecithin and/or bile salts
  • treatment:
    • administration of chenodeoxycholic acid (chenodiol)
    • surgical removal of gall bladder (cholecystectomy)