A patient with type IIb hyperlipidemia (elevated LDL and VLDL) is started on a statin. The mechanism by which statins increase LDL receptor expression involves:

• A Reduction of intracellular cholesterol activating SREBP-2 nuclear translocation ✓
• B Direct transcriptional activation of LDL receptor gene by the statin molecule
• C Upregulation of PCSK9 increasing LDL receptor recycling
• D Inhibition of ACAT increasing free cholesterol that activates LDL receptor

Explanation

Statins inhibit HMG-CoA reductase, reducing intracellular cholesterol synthesis. Low intracellular cholesterol allows SCAP (SREBP cleavage-activating protein) to escort SREBP-2 from the ER to the Golgi, where proteases (S1P, S2P) cleave it. The active nuclear form of SREBP-2 then binds sterol regulatory elements and upregulates LDL receptor gene transcription, increasing LDL uptake from plasma. PCSK9 actually promotes LDL receptor degradation; statins modestly increase PCSK9 (a limitation), which is why PCSK9 inhibitors are added for additional LDL lowering.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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