5th Unit / Ch 18 Cholesterol & Steroid Metabolism Flashcards
Cholesterol 18 1.1
In addition to de novo synthesis (self creation), what are the other two major sources of liver cholesterol, as shown?
Liver receives cholesterol from the diet via CM remnants and from peripheral tissues via HDLs .
Cholesterol 18 1.2
What does cholesterol do for membranes,
Liver, adrenal cortex, and the skin?
Cholesterol is a structural component of membranes,
the precursor of bile acids in the liver,
steroid hormones in the adrenal cortex,
and vitamin D in the skin.
Cholesterol 18 1.3
In cholesterol synthesis, which enzymatic steps are identical to those required for KB synthesis? What is different?
Two acetyl CoA → acetoacetyl CoA → HMG CoA are steps common to cholesterol and KB synthesis.
The difference is that the liver has two isozymes of HMG CoA synthase that convert acetoacetyl CoA to HMG CoA. The
mitochondrial isoenzyme is used for KB synthesis, and the cytosolic one is used for cholesterol synthesis.
Cholesterol 18 1.4
Why might patients with hypercholesterolemia be prescribed ezetimibe? Why should they include plant sterols
(phytosterols) in their diet?
Ezetimibe and phytosterols decrease intestinal absorption of dietary cholesterol (via different mechanisms).
Consequently, they have a hypocholesterolemic effect and are used to treat elevated blood cholesterol.
Cholesterol 18 2.1
What enzyme (denoted by the red question mark) is the rate-limiting, regulated enzyme in cholesterol biosynthesis?
The rate-limiting, regulated enzyme of cholesterol biosynthesis is HaMG CoA reductase .
Cholesterol 18 2.2
How is the enzyme regulated at the transcriptional level when intracellular cholesterol is low? How
else is it regulated?
When intracellular cholesterol is low , the SREBP–SCAP (sterol regulatory element–binding protein-2) complex of the ER membrane moves to the Golgi, where SREBP is sequentially cleaved to a soluble fragment (SREBP-2) that enters the nucleus, binds SRE regions on DNA, and functions as a TF that increases expression of HMG CoA reductase.
A rise in cholesterol inhibits this process. [Note: SREBP-1 upregulates FA and TAG synthesis.] Additional sterol-dependent regulation is the accelerated degradation of the reductase . Sterol-independent regulation includes phosphorylation of the reductase by AMPK. [Note: When AMPK is active, acetyl CoA is oxidized in the TCA cycle and not used in FA and cholesterol synthesis.]
Cholesterol 18 2.3
How do statins affect cholesterol biosynthesis?
- *Statins** are competitive inhibitors of HMG CoA reductase . Consequently, they increase the apparent K m of the enzyme (decrease the affinity of enzyme for
substrate) but do not affect the V max .
Bile Acids and Bile Salts 18 3.1
What enzyme (denoted by the red question mark) is the rate-limiting and regulated enzyme of BA synthesis?
How is the enzyme regulated?
The rate-limiting and regulated enzyme of BA synthesis is cholesterol 7- a -hydroxylase, a CYP enzyme of the SER in hepatocytes. [ Note: The products, the primary BAs, undergo hepatic conjugation with taurine or Gly and form conjugated BAs that are stored in the gallbladder and released by CCK. At the pH of bile, the conjugated derivatives are negatively charged, contributing to
their amphipathic nature, and are termed BSs. Intestinal bacteria can dehydroxylate them, generating
secondary BSs.]
Regulation is transcriptional: BAs (via a nuclear receptor) cause decreased transcription of the gene for the hydroxylase .
Bile Acids and Bile Salts 18 3.2
How does the amphipathic nature of BSs and TAG aid in dietary lipid emulsification?
The amphipathic nature of BSs is largely the result of hydroxylation, which creates a water-soluble face (that interacts with the aqueous environment) and a water-insoluble face
(that interacts with dietary lipids) that allow them to stabilize dietary lipid droplets (prevent their coalescence) as they become smaller ( emulsification ).
Bile Acids and Bile Salts 18 3.3
Why are agents such as cholestyramine that interfere with the enterohepatic circulation of BSs useful
in hypercholesterolemia treatment?
Over 95% of BSs are reabsorbed in the proximal ileum, returned to the liver, and reused
(enterohepatic circulation). Excretion of a small amount in stool is the primary mechanism by which cholesterol is removed from the body. [Note: BS deficiency can result in cholesterol stone formation (cholelithiasis).] Cholestyramine binds BSs, preventing their reabsorption and increasing the amount excreted. Consequently, more cholesterol is used for BA synthesis, thereby decreasing blood cholesterol levels.
Plasma Lipoproteins 18 4.1
What molecules are contained in the core of a LP, as shown? What are the sources of these molecules? Which LP is the largest? Which is densest?
TAGs and CEs, nonpolar molecules, are in the LP core. They come from exogenous (dietary) sources or from endogenous synthesis. CMs are the largest (and least dense) of
the LPs. HDLs are the densest (and smallest).
Plasma Lipoproteins 18 4.2
Compare and contrast CMs and VLDLs.
VLDLs are made in the liver and secreted into the blood, contain the structural protein apo B-100, obtain apo C-II and apo E from circulating HDLs, and carry endogenous
TAGs(and cholesterol) to most peripheral tissues where they are degraded in capillaries byendothelial LPLthat is activated byapo C-IIon the LP’s surface. The TAG-poor, CE-richLDLproduct is endocytosed byLDL receptors found on virtually all cells and
that recognize apo B-100.
Plasma Lipoproteins 18 4.2 Continued.
Compare and contrast CMs and VLDLs.
CMs are made in the small intestine and secreted first into the lymph then the blood, contain the structural protein apo B-48, and carry exogenous (dietary) TAGs to muscle and adipose tissue primarily. The TAG-poor, CE-rich CM remnant produced
by intravascular LPL- and apo CII-mediated degradation is endocytosed by remnant receptors found on hepatocytes and that recognize apo E.
[Note: IDLs (formed during VLDL catabolism) are endocytosed via receptors that recognize apo E.]
Plasma Lipoproteins 18. 4.4
What is the total cholesterol (C) if LDL-C = 136 mg/dl,
HDL-C = 45 mg/dl, and TAGs = 150 mg/dl?
Total C = LDL-C + HDL-C + TAG/5 . Therefore, 136 + 45 + 150/5 + 211 mg/dl.
TAG/5 is a measure of VLDL-C.
[Note: The goal value for total cholesterol is 200 mg/dl.]
Plasma Lipoproteins 18 5.1
What mediates the decrease in LDL receptor synthesis
when intracellular cholesterol is high, as shown?
Decreased LDL receptor synthesis when intracellular cholesterol is high is mediated by retention of the SREBP–SCAP complex in the ER membrane. This prevents
formation (in the Golgi) of SREBP-2, a TF that binds SREs
on DNA and increases expression of the gene for the LDL receptor. The gene for HMG CoA reductase, the rate-limiting enzyme of cholesterol synthesis, is regulated in the same way (see Card 18.2). [Note: Cytosolic ACAT esterifies
the excess cholesterol to CE for storage in cytosolic droplets.]
Steroid Hormones 18 6.1
What molecule (denoted by the red question mark) is the parent compound for all steroid hormones? What role does desmolase play in its synthesis?
Pregnenolone, derived from cholesterol, is the parent of all steroid hormones. Desmolase, a CYP enzyme (CYP11A, or P450scc) of the inner mitochondrial membrane catalyzes cholesterol hydroxylation and sidechain
cleavage (scc). This is the initial and rate-limiting step.
