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274) Which one of the following best describes the changes associated with activation of the low-density lipoprotein receptor (LDLR) pathway?

Decreased 3-hydroxy-3-methykl-glutaryl-CoA (HMG-CoA) reductase activity, increased acetyl-coenzyme A acetyltransferase (ACAT) activity, and decreased expression of LDL receptors. Increased HMG-CoA reductase activity, decreased ACAT activity, and decreased expression of LDLRs. Decreased HMG-CoA reductase activity, decreased ACAT activity, and decreased expression of LDLRs. Decreased HMG-CoA reductase activity, decreased ACAT activity, and increased expression of LDLRs. Increased HMG-CoA reductase activity, increased ACAT activity, and increased expression of LDLRs.

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• The low-density lipoprotein receptor (LDLR) mediates the endocytosis of cholesterol-rich LDL.

• After binding to the LDLR, LDL cholesterol undergoes receptor-mediated internalization, degradation by lysosomal hydrolases, and generation of LDL-derived cholesterol.

• Increased intracellular cholesterol inhibits de novo synthesis of cholesterol by suppressing the activity of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme.

• Increased intracellular cholesterol activates a cholesterol-esterifying enzyme (increased acetyl-coenzyme A acetyltransferase [ACAT]) to generate cholesteryl esters. Increased concentrations of free intracellular cholesterol are toxic. Cholesteryl esters are not toxic and can be stored.

• Increased intracellular cholesterol inhibits the transcription of the LDLR gene. The sterol-regulatory element binding protein is the major transcriptional regulator of the LDLR gene. It is inhibited by cholesterol and polyunsaturated fatty acids.

Goldstein JL, Brown MS: The LDL receptor.Arterioscler Thromb Vasc Biol 2009;29:431–438.

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Clinical Pathology: Clinical Chemistry

274) Which one of the following best describes the changes associated with activation of the low-density lipoprotein receptor (LDLR) pathway?

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