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Chapter 26: Lipids: Cholesterol Metabolism

You have been studying the pathway of cholesterol biosynthesis using a cell line derived from a human hepatoma. You discover that, unlike in nontransformed liver cells, the addition of oxysterols, such as 25-hydroxycholesterol, does not lead to reduced measurements of newly synthesized cholesterol. These observations indicate that normal regulation of an enzyme in cholesterol biosynthesis is defective in these cancer cells. Which of the following enzymes is the most likely candidate for this loss of regulation?

A. acetoacetyl-CoA thiolase (ACAT2)

B. 7-dehydrocholesterol reductase (DHCR7)

C. HMG-CoA reductase (HMGR)

D. HMG-CoA synthase

E. mevalonate kinase

Answer C: Oxysterols regulate the activity of the transcription factor SREBP-1c. When oxysterol or cholesterol levels are elevated, there is an inhibition of the release of SREBP-1c from the Golgi membrane, thereby, reducing the SREBP-1c-mediated transcriptional activation of numerous target genes including HMGR. Normal oxysterol regulation of SREBP-1c would lead to reduced cholesterol synthesis due, in part, to reduced expression of HMGR. Thus, continued transcriptional activation of target genes by SREBP-1c, even in the presence of oxysterols, would be measurable with continued cholesterol synthesis due to unregulated transcription of HMGR.

Activation of which of the following enzymes, involved in the regulation of cholesterol biogenesis, occurs in response to an altered ATP:ADP ratio?

A. AMP-activated kinase (AMPK)

B. HMG-CoA reductase phosphatase

C. protein phosphatase 2C

D. protein phosphatase inhibitor-1

E. protein kinase A (PKA)

Answer A: Regulation of HMG-CoA reductase (HMGR) is controlled primarily by a short-term regulatory cascade that results in phosphorylation of the enzyme. Once phosphorylated, HMGR is much less active and thus, cholesterol biosynthesis will be reduced. In order to return to a more active state, the phosphorylated sites on HMGR must be dephosphorylated. All of the enzyme choices listed are involved in regulation of HMGR activity, however, only AMP-activated kinase (AMPK) activity is affected by alteration in the ATP:ADP ratio in cells. When ATP levels fall, AMP levels will rise and AMPK becomes fully activated. Phosphorylation of HMGR by AMPK results in reduced cholesterol synthesis, which results in reduced ATP consumption.

The statin class of drugs that are currently used to control hypercholesterolemia function to lower circulating levels of cholesterol by which of the following mechanisms?

A. increasing the elimination of bile acids leading to increased diversion of cholesterol into bile ...

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