Reverse cholesterol transport (RCT) promotes the egress of cholesterol from peripheral tissues to the liver for biliary and fecal excretion. Although not demonstrated in vivo, RCT is thought to be impaired in patients with metabolic syndrome, in which liver steatosis prevalence is relatively high. Golden Syrian hamsters were fed a nonpurified (CON) diet and normal drinking water or a high-fat (HF) diet containing 27% fat, 0.5% cholesterol, and 0.25% deoxycholate as well as 10% fructose in drinking water for 4 wk. Compared to CON, the HF diet induced insulin resistance and dyslipidemia, with significantly higher plasma non-HDL-cholesterol concentrations and cholesteryl ester transfer protein activity. The HF diet induced severe liver steatosis, with significantly higher cholesterol and TG levels compared to CON. In vivo RCT was assessed by i.p. injecting ³H-cholesterol labeled macrophages. Compared to CON, HF hamsters had significantly greater ³H-tracer recoveries in plasma, but not HDL. After 72 h, ³H-tracer recovery in HF hamsters was 318% higher in liver and 75% lower in bile (P < 0.01), indicating that the HF diet impaired hepatic cholesterol fluxes. However, macrophage-derived cholesterol fecal excretion was 45% higher in HF hamsters than in CON hamsters. This effect was not related to intestinal cholesterol absorption, which was 89% higher in HF hamsters (P < 0.05), suggesting a possible upregulation of transintestinal cholesterol excretion. Our data indicate a significant increase in macrophage-derived cholesterol fecal excretion in a hamster model of metabolic syndrome, which may not compensate for the diet-induced dyslipidemia and liver steatosis.

H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After

Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glycaemic control in type 2 diabetes, but their benefits on reverse cholesterol transport (RCT) remain unknown. We evaluated the effects of DPP-4i sitagliptin 500 mg/kg/day on RCT in obese insulin-resistant CETP-apoB100 transgenic mice. Metformin 300 mg/kg/day orally was used as a reference compound. Both metformin and sitagliptin showed the expected effects on glucose parameters. Although no significant effect was observed on total cholesterol and high-density lipoprotein (HDL) cholesterol levels, sitagliptin, but not metformin, increased faecal cholesterol mass excretion by 132% (p < 0.001 vs. vehicle), suggesting a potent effect on cholesterol metabolism. Mice were then injected i.p. with (3) H-cholesterol labelled macrophages to measure RCT over 48 h. Compared with vehicle, sitagliptin significantly increased macrophage-derived (3) H-cholesterol faecal excretion by 39%. Administration of (14) C-cholesterol labelled olive oil orally showed a significant reduction of (14) C-tracer plasma appearance over time with sitagliptin, indicating that this drug promotes RCT through reduced intestinal cholesterol absorption.

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IntroductionDyslipidemia is a major characteristic of insulin-resistant and type 2 diabetic patients and contributes to the increased cardiovascular risk in these individuals. Although LDL-cholesterol therapies are known to reduce the risk of cardiovascular events, 1 additional therapies are required to further prevent cardiovascular diseases. As HDL-cholesterol (HDL-c) levels are inversely correlated with cardiovascular risk 2 and are known to be lower in diabetic dyslipidemia, a considerable interest has focused on the development of novel therapies that raises HDL-c. 3Th e cardioprotective eff ect of HDL-c would be related, at least in part, to its major role in macrophage-to-feces reverse cholesterol transport (RCT). Th is physiological process mediates the transport of excess cholesterol by HDL from peripheral tissues back to the liver for uptake of cholesteryl esters by the scavenger receptor class B type I (SR-BI). In the liver, cholesteryl esters are then metabolized as free cholesterol or bile acids for further excretion into the bile and ultimately in the feces. 4 In humans, another RCT pathway is represented by the cholesteryl ester transfer protein (CETP), which transfers cholesteryl esters from HDL to apolipoprotein (apo) B-containing lipoproteins VLDL/ LDL for further hepatic uptake by the LDL-receptor. Increased CETP activity is thought to drive the lowering of HDL-c levels in diabetic dyslipidemia.5 Hence, dyslipidemia would impair RCT and inhibition of CETP thus represents a relevant therapeutic strategy to raise HDL-c levels and potentially improve RCT. However, the CETP pathway is thought to be a major route for human RCT,6 since it represents approximately 80% of the plasma cholesteryl esters output.7 Hence, one of the major concerns with the development of CETP inhibitors is whether inhibiting the CETP pathway would alter the rate of RCT in vivo .As no clinical data are available regarding the eff ects of CETP inhibition on human RCT, the use of animal models expressing CETP represents a relevant strategy to evaluate the eff ects of CETP inhibitors. Although the molecular mechanisms of RCT have been extensively investigated in mice, substantial diff erences exist between mouse and human RCT (e.g., mouse does not express CETP). However, introducing the expression of human CETP in mouse has been shown to induce a more human-like profi le. 8,9 In this line, recent studies in transgenic mice that express both human apoB100 and human CETP (CETP-apoB100 mice) have demonstrated the relevance of this animal model to evaluate the eff ects of compounds raising HDL-c, such as niacin 10 and CETP inhibitor torcetrapib.11 On another note, mouse fed a 60% high-fat diet has been described as a model of obesity and type 2 diabetes. 12Hence, to investigate the eff ects of CETP inhibition on RCT in the face of insulin resistance and dyslipidemia, we used CETP-apoB100 mice fed a 60% high-fat diet over 3 months and evaluated the eff ects of the CETP inhibitor torcetrapib in this animal model. Methods Animals and...