ATHEROSCLEROSIS: CELL BIOLOGY AND LIPOPROTEINS Edited by Andrew Newby and Mohamad NavabRe-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulationYamashita, Shizuyaa,b,c; Matsuzawa, YujidAuthor Information aDepartment of Community Medicine bDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita cRinku General Medical Center, Izumisano dSumitomo Hospital, Kita-ku, Osaka, Japan Correspondence to Shizuya Yamashita, MD, PhD, FAHA, FJCC, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan. Tel: +81 6 6879 3633; fax: +81 6 6879 3634; e-mail: [email protected] Current Opinion in Lipidology: October 2016 - Volume 27 - Issue 5 - p 459-472 doi: 10.1097/MOL.0000000000000332 Buy Metrics Abstract Purpose of review To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. Recent findings CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver. Summary For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.