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9 Cards in this Set

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List the functions of cholesterol in the human body
1. Cell membranes
2. Steroid hormone precursor
Outline cholesterol synthesis and discuss the branch-point at the level of farnesyl-PP
1. HMG-CoA Reductase synthesizes Mevalonate from Acetyl-CoA an Acetoacetyl-CoA in the rate determining step.
2. Mevalonate is converted to 5-C Isopentyl PPi (Active isoprene)
3. Synthesis of a 10-C Geranyl PPi and then a 15-C Farnesyl PPi from Isopentyl PPis
4. Farnesyl PPi is a branch point either generating CoQ, Doliqol or Cholesterol.
5. Synthesis of 30-C Squalene from two Farnesyl PPis
6. Conversion to 27-C Cholesterol in 27 individual steps.
Indicate the biochemical basis of Smith-Lemli-Opitz syndrome (SLOS)
- Can't synthesize cholestrol due to a 7-dehydrocholesterol-7-reductase deficiency
- Autosomal recessive (congenital)
- Pathology: heart defects, limb malformation and microcephaly with mental retardation.
Explain how the HMG-CoA to Mevalonate pathway is regulated at the level of HMG-CoA reductase
1. Hormonal Regulation - short term
- Glucagon enhances its phosphorylation (inactive)
- Insulin enhances its dephosphorylation (action)

2. Allosteric Regulation - long term
- Increases the rate at which the enzyme is degraded through ubiquination
- up-regulation of transcription by binding SCAP-SREBP complex to SRE site on DNA
- down-regulation of transcription by encouraging SCAP to bind to a SREBP competitor
Outline bile acid synthesis and its regulation; indicate the rate limiting step in bile acid synthesis
- Most common bile acids are Cholic acid and Chenodeoxycholic acid
- 70-80% of hepatic cholesterol is converted to bile
- Bile acid/salts are derived from cholesterol catabolism with phospholipids and free cholesterol
- The rate-limiting step is the inroduction of a hydroxyl group at carbon-7 by cholesterol 7-α-hydroxylase.
Describe the conjugation of primary and secondary bile acids in the liver and its significance
Before leaving the liver, bile salts must be conjugated with glycne or taurine into sodium or potassium salts to increase their solubility.

Bacteria in the gut deconjugate them, making secondary bile acids which return to the liver for reconjugation.
Discuss bile composition and predict biochemical reasons for gallstone formation
Bile is made of bilirubin (25% mono- and 75% di-glucuronide with traces of unconjugated bilirubin) from cholesterol and phospolipid.

Cholesterol-rich stones form when:
1. The liver secretes more cholesterol than phospholipid, which forms around an insoluble nucleus.
2. by interference of the enterohepatic circulation (severe disease or obstruction),
3. a severe decrease in bile synthesis
4. as the side-effect of fibrates that increase cholesterol secretion.
Describe the biochemical basis for use of chenodeoxycholic acid for management of cholelithiasis
It causes a decrease in cholesterol saturation of bile, leading to gradual dissolution of stones before being reabsorbed.