Objective-The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. Methods and Results-E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (ϩ43%; PϽ0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both E3L and CETP.E3L mice (PϽ0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of CETP.E3L mice had reduced capacity (Ϫ39%; PϽ0.05) to induce SR-BI-mediated cholesterol efflux from Fu5AH cells than plasma of E3L mice. After 19 weeks on the Western-type diet, CETP.E3L mice showed a 7.0-fold increased atherosclerotic lesion area in the aortic root compared with E3L mice (PϽ0.0001). Conclusions-CETP expression in E3L mice shifts the distribution of cholesterol from HDL to VLDL/LDL, reduces plasma-mediated SR-BI-dependent cholesterol efflux, and represents a clear pro-atherogenic factor in E3L mice. We anticipate that the CETP.E3L mouse will be a valuable model for the preclinical evaluation of HDL-raising interventions on atherosclerosis development. Key Words: CETP Ⅲ cholesterol efflux Ⅲ hyperlipidemia Ⅲ reverse cholesterol transport Ⅲ transgenic mice C ardiovascular disease (CVD) is the leading cause of death in the Western world and its prevalence is increasing in Eastern Europe and developing countries. 1 The main cause of CVD is atherosclerosis, characterized by the combination of chronic inflammation and/or hyperlipidemia. 1 Both low high-density lipoprotein (HDL) cholesterol plasma levels and high very-low-density lipoprotein (VLDL)/lowdensity lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerosis development. 2 The ratio of VLDL/LDL to HDL is to a great extent affected by the cholesteryl ester transfer protein (CETP). 3 CETP is a transfer factor that mediates the exchange of cholesteryl esters (CE) and triglycerides (TG) between the apoB-containing lipoproteins (ie, chylomicrons, VLDL, and LDL) and HDL in plasma. 3 As such, CETP may be antiatherogenic by facilitating reverse cholesterol transport (RCT) from peripheral tissues to the liver via the VLDL/LDL pathway. Another potential role of CETP in RCT has recently been supported by the observation that CETP mediates HDL-CE uptake by hepatocytes independently of SR-BI and the LDL receptor (LDLr) in vitro. 4 However, CETP may be pro-atherogenic by enhancing the levels of VLDL/LDL with concomitant reduction of anti-atherogenic HDL levels.Many studies in humans have been performed regarding the association between CETP and lipoprotein levels and the subsequent development ...

Objective-Niacin potently decreases plasma triglycerides and LDL-cholesterol. In addition, niacin is the most potent HDL-cholesterol-increasing drug used in the clinic. In the present study, we aimed at elucidation of the mechanism underlying its HDL-raising effect. Methods and Results-In APOE*3Leiden transgenic mice expressing the human CETP transgene, niacin dose-dependently decreased plasma triglycerides (up to Ϫ77%, PϽ0.001) and total cholesterol (up to -66%, PϽ0.001). Concomitantly, niacin dose-dependently increased HDL-cholesterol (up to ϩ87%, PϽ0.001), plasma apoAI (up to ϩ72%, PϽ0.001), as well as the HDL particle size. In contrast, in APOE*3Leiden mice, not expressing CETP, niacin also decreased total cholesterol and triglycerides but did not increase HDL-cholesterol. In fact, in APOE*3Leiden.CETP mice, niacin dose-dependently decreased the hepatic expression of CETP (up to Ϫ88%; PϽ0.01) as well as plasma CETP mass (up to Ϫ45%, PϽ0.001) and CETP activity (up to Ϫ52%, PϽ0.001). Additionally, niacin dose-dependently decreased the clearance of apoAI from plasma and reduced the uptake of apoAI by the kidneys (up to Ϫ90%, PϽ0.01). yslipidemia is an important risk factor for the development of cardiovascular disease (CVD). Although lowering of LDL-cholesterol (C) by eg, statins reduces CVD risk by approximately 30%, substantial residual cardiovascular risk remains, even with very aggressive reductions in levels of LDL-C. [1][2][3] Because of clinical studies, which have shown that HDL-C, independently of LDL-C, is inversely correlated with the risk of CVD, 4,5 attention has shifted toward strategies for targeting HDL composition as adjunctive therapy to prevent and treat CVD. Current strategies to mildly increase HDL-C levels include aggressive overall lifestyle modification (ie, exercise, diet, weight loss, and smoking cessation), and modest increases in HDL-C levels are achieved with statins 6 and fibrates (5% to 10%). 7 Conclusion-Niacin markedly increases HDL-cholesterol in See accompanying article on page 1892Niacin (nicotinic acid, vitamin B3) has been described to exhibit lipid-modifying capacities already since the 1950s. Since then various (clinical) studies have shown the beneficial effects of niacin on plasma lipid levels. Treatment with niacin alone was associated with a 27% reduction in nonfatal myocardial infarction and it reduced all cause mortality by 11%. 8,9 In combination with colestipol (FATS trial) or simvastatin (HATS trial), niacin reduced cardiac events by as much as 80% to 90%. 10,11 These potent atherogenic properties of niacin are thought to be attributable to its marked HDLelevating effect (ϩ20% to ϩ30%), besides it potent effect on reducing plasma TG (Ϫ40% to Ϫ50%) and LDL-C (Ϫ20%). 7,12 In fact, niacin is currently the most effective therapy for elevating HDL-C.The mechanism underlying the ability of niacin to reduce the plasma (V)LDL level has been well studied. By selective binding to GPR109A on adipocytes, niacin suppresses hormone sensitive triglyceride lipase (HSL) activit...

Aims/hypothesis Cellular cholesterol accumulation is an emerging mechanism for beta cell dysfunction in type 2 diabetes. Absence of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) results in increased islet cholesterol and impaired insulin secretion, indicating that impaired cholesterol efflux leads to beta cell dysfunction. In this study, we aimed to determine the role of the LDL receptor (LDLr) in islet cholesterol uptake and to assess the contributions of cholesterol uptake compared with efflux to islet cholesterol levels. Methods Islet cholesterol and beta cell function were assessed in mice lacking LDLr (Ldlr

Besides their role in facilitating lipid absorption, bile acids are increasingly being recognized as signaling molecules that activate cell-signaling receptors. Targeted disruption of the sterol 12α-hydroxylase gene (Cyp8b1) results in complete absence of cholic acid (CA) and its derivatives. Here we investigate the effect of Cyp8b1 deletion on glucose homeostasis. Absence of Cyp8b1 results in improved glucose tolerance, insulin sensitivity, and β-cell function, mediated by absence of CA in Cyp8b1−/− mice. In addition, we show that reduced intestinal fat absorption in the absence of biliary CA leads to increased free fatty acids reaching the ileal L cells. This correlates with increased secretion of the incretin hormone GLP-1. GLP-1, in turn, increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1−/− mice. Thus, our data elucidate the importance of Cyp8b1 inhibition on the regulation of glucose metabolism.