Cholesterol Metabolism Flashcards
1
Q
describe the influx and efflux of cholesterol in the liver
A
2
Q
describe cholesterol synthesis overview
A
- 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
3
Q
name the sources of NADPH for cholesterol synthesis
A
similar to FA synthesis
- PPP
- Malic enzyme
4
Q
name the 5 basic steps of cholesterol synthesis
A
- synthesis of HMG-CoA
- synthesis of 6-C mevalonate
- formation of a 5-C isopentenyl pyrophosphate
- condensation of isoprenes to form squalene (C30)
- cyclization of squalene to lanosterol followed by cholesterol (C27) formation
5
Q
describe the synthesis of HMG-CoA
A
- 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)
6
Q
describe the synthesis of mevalonate
A
- 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
7
Q
describe the synthesis of cholesterol from mevalonate
A
- mevalonic acid –> 5-pyrophosphomevalonate (requires 2 ATP)
- 5-pyrophosphomevalonate –> isopentenyl pyrophosphate (IPP, 5C) uses 1 ATP
- IPP isomerized to 3,3-dimethylallyl pyrophosphate (DPP)
8
Q
describe how IPP gets to squalene
A
- 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
9
Q
describe how squalene ——-> cholesterol
A
-
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
10
Q
describe the importance of geranyl-groups, farnesyl groups and FPP
A
- 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
11
Q
describe cause of Smith-Lemli-Optiz Syndrome (SLOS)
A
- 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
12
Q
name clinical signs of SLOS
A
- autosomal recessive disorder
- heart defects, malformation of limbs, growth retardation, microcephaly
- cholesterol administration helps with growth but not CNS defects due to embryonic microcephaly
13
Q
describe the degradation of cholesterol
A
- 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
14
Q
name the 2 most abundant organic components of bile
A
- phosphatidylcholine (lecithin) and bile salts are most abundant organic components of bile
- also contains cholesterol, bilirubin
15
Q
describe the synthesis of bile acids
A
- 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
