Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice

Abstract

Objective-Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity. Methods and Results-Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098Ϯ7486 m 2 . No lesions greater than 1000 m 2 were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL. Key Words: cholesterol Ⅲ FPLC Ⅲ VLDL Ⅲ LDL Ⅲ HDL obesity C holesteryl ester transfer protein (CETP) is a glycoprotein that catalyzes the transfer of neutral lipids between the plasma lipoproteins. In this respect, this enzyme is involved in at least one arm of reverse cholesterol transport (RCT), an antiatherogenic process by which cholesterol is cleared from peripheral tissues. 1 Even so, the atherogenic nature of CETP has been the subject of much debate because both increased and decreased CETP expression have been linked to elevated risk and incidence of vascular disease. 2 Thus, the atherogenic nature of CETP is thought to depend on the metabolic context in which it influences lipoprotein metabolism. Conclusions-TheObesity is a metabolic condition afflicting more than one third of the population of the United States. 3 Obesity is accompanied by both a mild increase in vascular disease complications 4 as well as elevated plasma CETP activity. [5][6][7][8][9] It is unclear whether this perturbation in CETP activity contributes to altered lipoprotein profiles and elevated vascular disease risk or is a normal consequence of elevated cholesterol levels observed in these patients. 5,10 Interestingly, obese patients with type 2 diabetes have a higher risk of vascular disease complications, 11 higher circulating cholesterol levels, 5,10 and depressed levels of plasma CETP concentrations 5,12 compared with obese nondiabetic controls. This suppressive effect of diabetes on plasma CETP is not apparent in nonobese individuals. [13][14][15][16] We have hypothesized that depressed plasma CETP levels in obese patients with diabetes may hinder the clearance of the high levels of peripheral cholesterol that accompany obesity and contribute to elevated atherosclerosis in these patients.The purpose of this study was to examine the effects of overexpressing CETP...

Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk?

“…In other studies, expression of the CETP gene has been reported to have an antiatherogenic effect in db/db obese diabetic mice, 20 in lCAT transgenic mice, 21 in ovariectomized mice, 22 in testosterone-deficient mice, 23 and in apoC-III transgenic mice with hypertriglyceridemia. 24 In the last study, however, it was also reported that expression of the Cetp gene was proatherogenic in Figure 1.…”

“…Mice fed an atherogenic diet 14 ApoE knockout mice 15 LDL receptor knockout mice 15 ApoC-III transgenic mice with normal plasma triglyceride levels 24 ApoE3-Leiden mice 16 Aypertensive rats 17 Expression of CETP in rodents had no effect on atherosclerosis SR-B1 knockout mice 18 Expression of CETP in rodents decreased atherosclerosis db/db obese, diabetic mice 20 LCAT transgenic mice 21 Ovariectomized mice 22 Testosterone-deficient mice 23 ApoC-III transgenic mice with hypertriglyceridemia 24 B. Rabbits (rabbits have a high natural level of CETP activity) Inhibition of CETP in rabbits decreased susceptibility to diet-induced atherosclerosis in:…”

New Era of Lipid-Lowering Drugs

“…Rodents lack CETP (Ha and Barter, 1982) and are naturally resistant to the development of atherosclerosis. Transgenic expression of the Cetp gene in mice and rats has generated conflicting and modeldependent results, with some studies supporting the proposition that CETP is proatherogenic (Marotti et al, 1993;Herrera et al, 1999;Plump et al, 1999;Westerterp et al, 2006;Hildebrand et al, 2010;Kühnast et al, 2015), whereas others suggest that CETP has no effect or is antiatherogenic (Hayek et al, 1995;Föger et al, 1999;Cazita et al, 2003;MacLean et al, 2003;Casquero et al, 2006).…”

Therapeutic modulation of the natural history of coronary atherosclerosis: lessons learned from serial imaging studies

“…Transgenic mice have been engineered to express CETP, resulting in the development of atherosclerosis (86,87). Different murine models have provided discordant results, with some indicating that CETP is antiatherogenic (88)(89)(90), and others that it is proatherogenic (91)(92)(93). Rabbits are highly susceptible to the development of diet-induced atherosclerosis, and have a naturally high level of CETP.…”