The committed step in cholesterol biosynthesis is catalysed by HMG-CoA reductase. Statins competitively inhibit this enzyme. Which downstream effect is responsible for the greatest increase in LDL receptor expression following statin therapy?

• A Reduced intracellular cholesterol activates SREBP-2, which upregulates LDL receptor gene transcription ✓
• B Accumulation of HMG-CoA directly binds the LDL receptor promoter
• C Increased mevalonate activates PCSK9 which recycles LDL receptors
• D Reduced farnesyl pyrophosphate prevents RAS prenylation, indirectly upregulating the receptor

Explanation

When intracellular cholesterol falls after statin-mediated HMG-CoA reductase inhibition, the SCAP-SREBP-2 complex is no longer retained in the ER by Insig proteins. SREBP-2 is cleaved by S1P and S2P proteases in the Golgi, translocates to the nucleus, and transcriptionally upregulates the LDL receptor gene. More LDL receptors on hepatocyte surfaces then clear LDL-C from plasma. PCSK9 actually degrades LDL receptors; statins modestly increase PCSK9, partially offsetting the receptor upregulation.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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