Cholesterol Metabolism

Question 1

describe the influx and efflux of cholesterol in the liver

Answer 1

Question 2

describe cholesterol synthesis overview

Answer 2

• 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

Question 3

name the sources of NADPH for cholesterol synthesis

Answer 3

similar to FA synthesis

• PPP
• Malic enzyme

Question 4

name the 5 basic steps of cholesterol synthesis

Answer 4

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

Question 5

describe the synthesis of HMG-CoA

Answer 5

• 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)

Question 6

describe the synthesis of mevalonate

Answer 6

• 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

Question 7

describe the synthesis of cholesterol from mevalonate

Answer 7

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

Question 8

describe how IPP gets to squalene

Answer 8

• 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

Question 9

describe how squalene ——-> cholesterol

Answer 9

• 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

Question 10

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

Answer 10

• 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

Question 11

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

Answer 11

• 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

Question 12

name clinical signs of SLOS

Answer 12

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

Question 13

describe the degradation of cholesterol

Answer 13

• 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

Question 14

name the 2 most abundant organic components of bile

Answer 14

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

Question 15

describe the synthesis of bile acids

Answer 15

• 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

Question 16

describe conjugated bile salts

Answer 16

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

Question 17

describe the aciton of intestinal flora on bile salts

Answer 17

• 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

Question 18

describe the enterohepatic circulation of bile salts

Answer 18

• 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

Question 19

describe cholesterol gallstone disease (cholelithiasis)

Answer 19

• 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)