Cholesterol is a membrane component and precursor to bile acids, vitamin D, and steroid hormones. It is obtained through the diet and synthesized de novo in the liver through a multi-step process using acetyl-CoA. Cholesterol levels are regulated by feedback inhibition of HMG-CoA reductase. Excess cholesterol is excreted in bile as bile acids through enterohepatic circulation. Genetic disorders of cholesterol metabolism can cause severely elevated cholesterol levels and premature cardiovascular disease.
4. Dietary cholesterol
◦ From chylomicron remnants
Cholesterol from extra-hepatic tissues
◦ Reverse cholesterol transport via HDL
Chylomicron remnants
IDL
De novo synthesis
5. VLDL -> LDL
◦ Transport to extra-hepatic tissues
Direct excretion into bile
◦ Gallstones commonly are precipitates of cholesterol
Occurs when bile becomes supersaturated with cholesterol
Obesity, biliary stasis, infections
Bile acid synthesis and excretion into bile
7. O OH O
−
O C CH2 C CH2 C SCoA
CH3
hydroxymethylglutaryl-CoA
Hydroxymethylglutaryl-coenzyme A (HMG-CoA)
is the precursor for cholesterol synthesis.
HMG-CoA is also an intermediate on the pathway for
synthesis of ketone bodies from acetyl-CoA.
The enzymes for ketone body production are located in
the mitochondrial matrix.
HMG-CoA destined for cholesterol synthesis is made by
equivalent, but different, enzymes in the cytosol.
8. O O
H3C C CH2 C SCoA
H2 O + O acetoacetyl-CoA
H3 C C SCoA
acetyl-CoA HMG-CoA
HSCoA Synthase
O OH O
−
O C CH2 C CH2 C SCoA
CH3
hydroxymethylglutaryl-CoA
HMG-CoA is formed by condensation of acetyl-CoA &
acetoacetyl-CoA, catalyzed by HMG-CoA Synthase.
HMG-CoA Reductase catalyzes production of mevalonate
from HMG-CoA.
9. Formation of HMG CoA (cyto)
◦ Analogous to KB synthesis (mito)
Conversion of HMG CoA to activated
isoprenoids
10. Condensation of
isoprenoids to
squalene
◦ Six isoprenoids
condense to form 30-C
molecue
12. All carbons from acetyl-CoA
Requires NADPH, ATP, & O
2
Stages
◦ One: forms HMG CoA
◦ Two: forms activated 5 carbon intermediates (isoprenoids)
◦ Three: six isoprenoids form squalene
◦ Four: squalene + O2 form cholesterol
13. Cellular cholesterol content exerts transcriptional control
◦ HMG-CoA reductase
Half life = 2 hours
◦ LDL-receptor synthesis
Nutrigenomics:
◦ interactions between environment and individual genes and how
these interactions affect clinical outcomes
15. Covalent Modification of
HMG-CoA Reductase
◦ Glucagon stimulates
adenyl cyclase producing
cAMP
◦ cAMP activates protein
kinase A
◦ Inactivates HMG-CoA
reductase
Fasting inhibits
cholesterol synthesis
16. Major excretory form of cholesterol
◦ Steroid ring is not degraded in humans
◦ Occurs in liver
Bile acid/salts involved in dietary lipid digestion
as emulsifiers
17. Primary bile acids
◦ Good emulsifying agents
All OH groups on same side
pKa = 6 (partially ionized)
Conjugated bile salts
◦ Amide bonds with glycine
or taurine
◦ Very good emulsifier
pKa lower than bile acids
18. Hydroxylation
◦ Cytochrome P-450/mixed
function oxidase system
Side chain cleavage
Conjugation
Secondary bile acids
◦ Intestinal bacterial
modification
Deconjugation
Dehydroxylation
Deoxycholic acid
Lithocholic acid
19. Enterohepatic circulation
◦ 98% recycling of bile acids
Cholestyramine
Treatment
◦ Resin binds bile acids
◦ Prevents recycling
◦ Increased uptake of LDL-C
for bile acid synthesis
23. 8 yo girl
◦ Admitted for heart/liver transplant
History
◦ CHD in family
◦ 2 yo xanthomas appear on legs
◦ 4 yo xanthomas appear on elbows
◦ 7 yo admitted w/ MI symptoms
[TC] = 1240 mg/dl
[TG] = 350 mg/dl
[TC]father = 355 mg/dl
[TC]mother = 310 mg/dl
◦ 2 wks after MI had coronary bypass surgery
◦ Past year severe angina & second bypass
◦ Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000
mg/dl
24. Raised, waxy
appearing, often yellow
skin lesions (shown
here on knee)
◦ Associated with hyperlipidemia
Tendon xanthomas common
on Achilles and hand
extensor tendons
25. Xanthomas of the eyelid
Eruptive Xanthomas -generally associated with
-generally associated with hypercholesterolemia
hypertriglyceridemia