A patient is started on a statin for hyperlipidemia. The primary biochemical mechanism involves competitive inhibition of HMG-CoA reductase, which leads to compensatory upregulation of hepatic LDL receptors. At which subcellular site does HMG-CoA reductase primarily reside, and what signals its degradation?

• A Cytosol; degraded by proteasomes when cholesterol is high
• B Mitochondrial matrix; cleaved by matrix metalloprotease when NADPH is limiting
• C Peroxisome; ubiquitinated by SCAP when oxysterols accumulate
• D Smooth endoplasmic reticulum (SER); INSIG-mediated proteasomal degradation when sterols are high ✓

Explanation

HMG-CoA reductase is an integral membrane enzyme of the smooth endoplasmic reticulum. When cellular sterols (cholesterol and oxysterols) are abundant, they bind INSIG proteins on the ER membrane; INSIG then promotes ubiquitin-proteasome-mediated degradation of HMG-CoA reductase, reducing its half-life from ~12 h to ~1 h. This feedback prevents excessive cholesterol synthesis. SCAP is involved in SREBP processing, a parallel regulatory pathway.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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