In cholesterol biosynthesis, statins inhibit HMG-CoA reductase, the rate-controlling enzyme. Following statin therapy, the compensatory upregulation of LDL receptors in hepatocytes is mediated by which molecular mechanism?

• A SREBP-2 remains bound to SCAP-Insig complex and cannot reach the Golgi
• B Decreased intracellular cholesterol releases SCAP from Insig, allowing SCAP-SREBP-2 transport to Golgi where SREBP-2 is cleaved and activates LDL receptor gene transcription ✓
• C Statins directly bind the LDL receptor promoter and activate transcription
• D Statins activate PCSK9 to increase LDL receptor recycling

Explanation

When intracellular cholesterol falls (due to statin-mediated HMG-CoA reductase inhibition), the SCAP-SREBP-2 complex is released from Insig retention proteins in the ER and translocates to the Golgi. There, S1P and S2P proteases sequentially cleave SREBP-2, releasing its N-terminal transcription factor domain, which travels to the nucleus and activates sterol regulatory element (SRE) sequences in the LDL receptor gene promoter. This compensatory upregulation of LDL receptors is the principal mechanism by which statins lower plasma LDL-C.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.