CETP (Cholesteryl Ester Transfer Protein Lipid Exchange Gene)
CETP (cholesteryl ester transfer protein; HGNC:1869, NCBI Gene ID 1071) is a human locus mapped to chromosome band 16q13 that encodes plasma boomerang-shaped glycoprotein CETP (476 mature aa; 74 kDa). CETP acts in heterotypic exchange of cholesteryl esters from HDL for triglycerides from VLDL/LDL, together with APOA1 (Apolipoprotein A-I Gene), APOB (Apolipoprotein B Gene), and LDLR (LDL Receptor Gene). Encodes cholesteryl ester transfer protein, which transfers cholesteryl esters from HDL to atherogenic ApoB-containing lipoproteins.
Genomic Organization & Cytogenetic Locus: 16-exon gene on chromosome 16q13 driven by an LXR/RXR sterol-responsive promoter, encoding a 476-amino-acid hydrophobic tunnel protein of the BPI/LBP/PLUNC family that accommodates two cholesteryl ester or triglyceride molecules and two plugging phospholipids within a 60-angstrom internal cavity.
Cellular & Tissue Expression Profile: Secreted into plasma primarily by hepatic Kupffer cells and hepatocytes as well as white adipocytes and spleen macrophages (notably present in humans, primates, and rabbits, but naturally absent in mice and rats).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Bridges cardioprotective HDL particles and atherogenic ApoB-100/ApoB-48 lipoproteins (VLDL, IDL, LDL, chylomicrons) to catalyze the equimolar bidirectional heteroexchange of cholesteryl esters out of HDL into VLDL/LDL in exchange for triglycerides moving into HDL, thereby depleting HDL-cholesterol and enriching LDL/VLDL with cholesterol.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Loss-of-function variants (including the East Asian splicing mutation Int14+1G>A, p.Asp442Gly, and the longevity-associated p.Ile405Val allele) markedly elevate HDL-cholesterol while reducing LDL-cholesterol and plasma ApoB levels, correlating in Mendelian randomization studies with reduced coronary heart disease and ischemic stroke risk proportional to ApoB reduction.
Therapeutic & Clinical Pharmacology: After early CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) failed or showed modest benefit (anacetrapib), the highly potent next-generation oral CETP inhibitor obicetrapib is in late-stage clinical development for lowering LDL-cholesterol, ApoB, and Lp(a).