A 45-year-old woman with xanthelasma and corneal arcus has a fasting lipid profile showing: total cholesterol 320 mg/dL, LDL 260 mg/dL, HDL 55 mg/dL, TG 25 mg/dL. Her heterozygous sibling has LDL of 250 mg/dL. The defect is in the LDL receptor gene causing absent receptor protein. Treatment with rosuvastatin increases LDL receptor expression. Why is statin therapy partially effective in receptor-negative (null allele) familial hypercholesterolemia heterozygotes compared to homozygotes?

• A Statins directly inhibit LDL receptor degradation by PCSK9 independently of receptor gene expression
• B Statins activate the alternate scavenger receptor pathway (SR-B1) to compensate for absent LDL receptors
• C Heterozygotes retain one functional allele; statins upregulate LDL receptor transcription via SREBP-2 activation on the normal allele ✓
• D Statins reduce hepatic VLDL secretion, indirectly decreasing LDL production without LDL receptor involvement

Explanation

In heterozygous familial hypercholesterolemia with one null allele, the patient has one functional LDL receptor allele. Statin-mediated inhibition of HMG-CoA reductase reduces intracellular cholesterol, activating SREBP-2 (sterol regulatory element-binding protein 2) through its SCAP-mediated cleavage. Activated SREBP-2 upregulates transcription of the remaining functional LDL receptor gene, increasing LDL receptor expression and cholesterol clearance. In homozygous receptor-negative patients (null/null), neither allele can be upregulated, making statins far less effective. This is why LDL apheresis or lomitapide/evinacumab are needed for homozygous FH. Understanding SREBP-2 regulation is central to statin pharmacology.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.