CETP

**Function:** CETP is a hydrophobic glycoprotein made mainly in the liver and secreted into plasma, where it is bound to HDL. It mediates a 1:1 heteroexchange. Cholesteryl esters (CE) move from HDL to apoB-containing particles (VLDL, IDL, LDL). Triglycerides (TG) move from VLDL to HDL. CE in HDL come from LCAT, which is activated by apoA-I and esterifies free cholesterol. This is part of reverse cholesterol transport.

**Net effects of CETP activity:** - HDL-C falls, and HDL becomes TG-rich. Hepatic lipase and lipoprotein lipase then hydrolyze that TG, leaving small HDL that is cleared faster. - LDL and VLDL remnants gain CE, which is potentially more atherogenic. - Hypertriglyceridemia drives more CETP-mediated exchange. This is why high TG goes with low HDL and small dense LDL, as in metabolic syndrome and diabetes.

**Lipoprotein enzymes and proteins (high-yield):** - LCAT (activated by apoA-I) esterifies cholesterol on HDL. - LPL (activated by apoC-II) hydrolyzes TG in chylomicrons and VLDL. - Hepatic lipase hydrolyzes TG in IDL and HDL. - ABCA1 effluxes cholesterol to nascent HDL (defective in Tangier disease). - SR-B1 mediates selective hepatic uptake of HDL cholesterol. - CETP exchanges CE and TG between HDL and apoB lipoproteins.

**CETP deficiency:** - Loss-of-function mutations are autosomal recessive and the best-known cause is in Japanese populations. They cause markedly elevated HDL-C (often >100 mg/dL) and large, CE-rich HDL particles. LDL-C is usually low-normal. - Cardiovascular risk effects are inconsistent. Some cohorts show increased risk despite high HDL, which supports the idea that HDL function matters more than HDL level. Mendelian randomization suggests that CETP variants lowering CETP activity also lower LDL-C and apoB, and this is associated with lower CV risk.

**CETP inhibitors (drug class):** - Mechanism: inhibition blocks CE transfer, which raises HDL-C and lowers LDL-C and apoB to varying degrees. - Torcetrapib: ILLUMINATE trial stopped early for increased mortality and CV events. Off-target effects included raised blood pressure and aldosterone. - Dalcetrapib: dal-OUTCOMES showed no benefit. - Evacetrapib: ACCELERATE showed no CV benefit despite a large HDL increase and an LDL reduction. - Anacetrapib: REVEAL showed a modest reduction in major coronary events, consistent with the non-HDL-C/apoB lowering rather than the HDL rise. It accumulates in adipose tissue. - Obicetrapib: a newer agent that lowers LDL-C and apoB substantially, including as an add-on to statins. The CV outcomes trial (PREVAIL) is ongoing or reporting, so check current status. - Boards take-home: raising HDL-C pharmacologically has not reduced CV events. Benefit tracks with the degree of apoB/non-HDL lowering.

**Exam pearls:** - CETP moves CE from HDL to VLDL/LDL, and TG the other way. Inhibition causes high HDL and lower LDL. - Familial hyperalphalipoproteinemia (high HDL) can result from CETP deficiency. - Low HDL is seen with high TG, smoking, obesity, and insulin resistance, with CETP activity contributing. - Don't confuse CETP with LCAT, LPL, hepatic lipase, or MTP (MTP loads apoB with lipid, and its deficiency causes abetalipoproteinemia).