cholesteryl ester transfer protein

CETP is synthesized primarily in the liver and adipose tissue and circulates in plasma bound to HDL particles. Its main function is to mediate the heteroexchange of neutral lipids between lipoprotein particles: it transfers cholesteryl esters from HDL to apoB-containing lipoproteins (LDL and VLDL) in exchange for triglycerides. This process is a key step in reverse cholesterol transport, the pathway by which excess cholesterol from peripheral tissues is returned to the liver for excretion via bile.

Pathophysiologically, CETP activity influences the balance between HDL and LDL cholesterol levels. Genetic deficiency of CETP (seen in some Japanese populations) results in markedly elevated HDL-C levels, historically thought to be atheroprotective, though the relationship between CETP activity and cardiovascular risk is complex and not entirely linear.

Clinically, CETP became a major pharmacologic target for developing drugs to raise HDL cholesterol and reduce atherosclerotic cardiovascular disease risk. Several CETP inhibitors have been developed and tested in large clinical trials: - Torcetrapib: increased HDL substantially but was associated with increased mortality and cardiovascular events, partly due to off-target effects causing hypertension and hyperaldosteronism; development was halted. - Dalcetrapib: raised HDL modestly but showed no significant reduction in cardiovascular events; development discontinued. - Evacetrapib: also failed to show clinical benefit despite favorable lipid changes. - Anacetrapib: showed a modest reduction in major coronary events in the REVEAL trial, though effects were partly attributed to LDL lowering rather than HDL raising; not approved due to modest benefit and concerns about drug accumulation in adipose tissue.

These trials have led to reconsideration of the "HDL hypothesis"—the idea that simply raising HDL cholesterol levels pharmacologically translates into cardiovascular benefit. The results suggest that the quality and functionality of HDL particles (e.g., their role in cholesterol efflux) may be more important than their absolute plasma concentration.

For board exams, know that CETP mediates transfer of cholesteryl esters from HDL to LDL/VLDL in exchange for triglycerides, that CETP deficiency raises HDL, and that CETP inhibitors have largely failed to show consistent cardiovascular benefit despite raising HDL and lowering LDL, highlighting the complexity of lipid-targeted therapies beyond statins.