Statins inhibit HMG-CoA reductase, but upregulate LDL receptors. The mechanism linking HMG-CoA reductase inhibition to LDL receptor upregulation is:
- A Statins directly bind the LDL receptor promoter, acting as transcriptional activators
- B Reduced intracellular cholesterol activates SREBP-2 (sterol-regulatory element binding protein), which transcriptionally upregulates LDLR gene expression ✓
- C Mevalonate pathway inhibition increases PCSK9 secretion, which upregulates LDLR
- D Statin-induced mevalonate deficiency activates AMPK, which phosphorylates and stabilises LDLR
Correct answer: B. Reduced intracellular cholesterol activates SREBP-2 (sterol-regulatory element binding protein), which transcriptionally upregulates LDLR gene expression
Explanation
When statins inhibit HMG-CoA reductase, intracellular cholesterol falls. SCAP (SREBP cleavage-activating protein) is no longer held in the ER by INSIG proteins; it escorts SREBP-2 to the Golgi where S1P and S2P proteases cleave and release the active SREBP-2 transcription factor. Active SREBP-2 translocates to the nucleus and upregulates LDLR (and HMG-CoA reductase itself). The net effect is increased cell-surface LDL receptors, lowering plasma LDL-C. Statins paradoxically also increase PCSK9, limiting their efficacy (basis for combination therapy).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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