**Genetics and Protein Structure:**
– The CETP gene is located on chromosome 16 (16q21).
– The crystal structure of CETP consists of a dimer of two TUbular LIPid (TULIP) binding domains.
– Each domain comprises 6 elements: 4 beta-sheets forming an extended superhelix and 2 flanking elements that may include alpha helices.
– CETP contains two of these domains that interact head-to-head via an interface made of 6 beta-sheets.
– The same protein fold is shared by other proteins like Bacterial Permeability Inducing proteins, phospholipid transfer protein, and long-Palate Lung, and Nasal Epithelium protein.
**Role in Disease and Pharmacology:**
– Rare mutations leading to reduced CETP function have been associated with accelerated atherosclerosis.
– Certain CETP gene polymorphisms have been linked to exceptional longevity and metabolic responses to nutritional interventions.
– Specific mutations affecting CETP levels have implications for coronary heart disease.
– Elaidic acid, a component of trans fat, can increase CETP activity.
– CETP inhibitors are being studied to improve HDL levels and potentially alleviate atherosclerosis and cardiovascular diseases.
**Research Studies and Clinical Trials:**
– Various studies have been conducted on the effects of CETP inhibitors on HDL cholesterol levels and atherosclerosis progression.
– Torcetrapib, a CETP inhibitor, showed promising results in increasing HDL levels and lowering LDL when co-administered with a statin.
– Trials with torcetrapib had mixed results in cardiovascular endpoints, leading to Pfizer halting clinical trials for safety reasons.
– Other CETP inhibitors like anacetrapib and evacetrapib faced challenges in trials, impacting their development and approval.
**Merck’s Inhibitor and Pfizer’s Decision:**
– Merck’s investigational CETP-Inhibitor, MK-0859, demonstrated positive effects on lipids but the company chose not to seek approval for its cholesterol treatment.
– Pfizer stopped all torcetrapib clinical trials due to safety concerns, highlighting the complexities of developing CETP inhibitors for cardiovascular health.
**Further Reading and Publication Details:**
– There are additional studies and articles discussing the role of CETP inhibition in dyslipidemia, raising HDL, and inhibiting atherosclerosis.
– Publications like those in The New England Journal of Medicine and Circulation have explored the efficacy and safety of various CETP inhibitors, providing valuable insights into their potential benefits and risks.
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
