Statins inhibit HMG-CoA reductase. Beyond reducing LDL-cholesterol synthesis, statins upregulate LDL receptors. The MOLECULAR mechanism by which statin-induced mevalonate depletion increases LDL receptor expression is:

• A Reduced cholesterol causes PCSK9 downregulation, preventing LDL receptor degradation
• B Reduced mevalonate activates LXR (liver X receptor), which transcriptionally induces the LDLR gene
• C Reduced geranylgeranyl pyrophosphate prevents RAS prenylation, activating p53-mediated LDLR transcription
• D Reduced intracellular cholesterol causes SCAP to escort SREBP2 from ER to Golgi, where it is cleaved to yield a transcription factor that activates LDLR gene promoter ✓

Explanation

When intracellular cholesterol is low, SCAP (SREBP cleavage activating protein) is no longer retained in the ER by INSIG-1/2; SCAP escorts SREBP2 to the Golgi where S1P and S2P proteases sequentially cleave SREBP2 to release its N-terminal transcription factor domain (nSREBP2). Nuclear nSREBP2 binds sterol response elements (SREs) in the LDLR gene promoter (and HMG-CoA reductase promoter), dramatically increasing LDLR expression. This upregulated LDLR clears more LDL from plasma, explaining statins' LDL-lowering efficacy. PCSK9 is also regulated by SREBP2 but as a feedback mechanism.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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