Mechanisms
In hypertensive rats made to express human CETP, blood pressure rose and fatty liver accelerated, yet atherosclerosis did not (Hypertens Res 2020)
Original title: Alterations of lipid metabolism, blood pressure and fatty liver in spontaneously hypertensive rats transgenic for human cholesteryl ester transfer protein
Rodents naturally lack CETP, which likely contributes to their atherosclerosis resistance, and studies of CETP-transgenic rodents have shown both pro- and anti-atherogenic effects. This study generated a new human CETP-transgenic strain on the background of spontaneously hypertensive rats (SHRs), which naturally develop hypertension and insulin resistance, to study the role of CETP in cardiometabolic disease combined with hypertension. On normal chow, CETP-transgenic SHRs had systolic blood pressure elevated by 20 to 37 mmHg throughout the study, accelerated fatty liver, reduced HDL cholesterol and elevated triglycerides, changes consistent with a proatherogenic CETP effect. Yet on a high-fat, high-cholesterol diet, despite these changes and a concurrent reduction in LDL cholesterol, no additional atherosclerosis progression was detected in the aorta or coronary arteries of CETP-transgenic SHRs. The authors conclude CETP has a multifaceted, not simply proatherogenic, effect on cardiometabolic phenotypes when combined with hypertension.
Original abstract
Cholesteryl ester transfer protein (CETP) mediates a step in reverse cholesterol transport, which channels cholesterol from peripheral tissues back to the liver. Mice and rats are CETP-deficient species, which assumedly contribute to rodent atherosclerosis resistance. Both pro- and anti-atherogenic effects have been shown in studies of CETP-transgenic rodent models thus far. As the results of pharmacological studies of CETP modification are largely controversial in humans, further knowledge about the impact of CETP on atherogenic phenotypes is required to evaluate its clinical utility for the prevention of cardiovascular and other organ damage associated with metabolic syndrome. Therefore, we newly generated a human CETP-transgenic (Tg[hCETP]) strain on the genetic background of spontaneously hypertensive rats (SHRs), which are characterized by the spontaneous occurrence of hypertension and insulin resistance. This allowed us to assess the in vivo role of CETP on cardiometabolic phenotypes in combination with hypertension. In Tg[hCETP] SHRs fed normal rat chow, systolic blood pressure was markedly elevated by 20-37 mmHg throughout the study period, and the development of fatty liver was accelerated with appreciable changes in the plasma lipid profile (HDL cholesterol reduction and triglyceride elevation). These phenotypic changes are in accordance with the assumption of proatherogenic effects inducible by the overexpression of CETP. However, with plasma LDL cholesterol levels concomitantly reduced, no apparent progression of atherosclerosis was detected in either the aorta or coronary arteries of Tg[hCETP] SHRs fed a high-fat, high-cholesterol diet. Our data provide new insight into the multifaceted regulation of cardiometabolic phenotypes via the modification of CETP.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.