Statins inhibit HMG-CoA reductase. Apart from reducing cholesterol synthesis, the indirect cellular consequence that paradoxically upregulates LDL receptor expression is:

• A Statin-induced PCSK9 secretion upregulates LDL receptor recycling
• B Statins directly bind LDLR promoter and enhance transcription
• C Reduced mevalonate decreases isoprenylation of Ras, reducing receptor internalisation
• D Reduced intracellular cholesterol activates SREBP-2, which increases LDLR gene transcription ✓

Explanation

When intracellular cholesterol falls due to HMG-CoA reductase inhibition by statins, sterol regulatory element-binding protein 2 (SREBP-2) is released from the ER complex (with Scap and INSIG proteins), transported to Golgi where it is cleaved by S1P and S2P proteases to release the active transcription factor. Active SREBP-2 translocates to the nucleus and binds sterol regulatory elements (SREs) in the LDLR gene promoter, upregulating LDL receptor expression. This increases hepatic LDL uptake from blood, the primary mechanism of statin-mediated LDL-C lowering. PCSK9 actually promotes LDLR degradation; statin-induced PCSK9 expression (a secondary effect) partially offsets statin efficacy, which is why PCSK9 inhibitors are combined with statins.

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

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