Dumas L.S.,French Institute of Health and Medical Research |
Dumas L.S.,University Grenoble Alpes |
Dumas L.S.,Advanced Accelerator Applications |
Briand F.,Physiogenex |
And 26 more authors.
Journal of Nuclear Medicine | Year: 2017
The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E2/2 mice. Methods: Apolipoprotein E2/2 mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice (n 5 15), we intravenously injected 3H-cholesteryl oleate-labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set (n 5 20), we used the imaging agent 99mTc-cAbVCAM1-5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set (n 5 21), we compared VCAM-1 expression with 99mTc-cAbVCAM1-5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate (P , 0.001 vs. control) after 3H-cholesteryl oleate-labeled LDL injection. At 96 h after injection, the hepatic fraction of 3H-tracer was 61% lower in mice treated with ezetimibe (P , 0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (P , 0.001). The antiatherogenic effect of ezetimibe monitored by 99mTc-cAbVCAM1-5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 6 0.04 vs. 1.87 6 0.11; P , 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with 99mTc-cAbVCAM1-5 uptake (r 5 0.75; P , 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol catabolism and LDL-derived cholesterol fecal excretion and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy.
Eddouks M.,Moulay Ismaï University |
Hebi M.,Moulay Ismaï University |
Ajebli M.,Moulay Ismaï University |
El Hidani A.,Moulay Ismaï University |
And 2 more authors.
Phytotherapie | Year: 2017
The anti-diabetic activities of Capparis spinosa (Cs) and Calamintha officinalis Moench (Co) were investigated in a diabetes mellitus model of mouse (high fat diet [HFD]), showing a pre-diabetic state. Decoction of the plants permits to obtain aqueous extracts (CoAE and CsAE). The administration of the aqueous extracts (CoAE 100 mg/kg and CsAE 100 mg/kg) and the aqueous extracts treated with heat (CoAE 100 mg/kg and CsAE 100 mg/kg) during 3 weeks showed an anti-diabetic activity, a loss of weight as well as a decrease in the free fatty acid plasmatic concentrations. The aqueous extracts were extracted using two different solvents, dichloromethane, and butanol, producing three fractions of each extract. The anti-diabetic and hypolipidemic activities observed by CoAE (100 mg/kg) treatment were noticed in mice treated with the free water fraction (CoER 100 mg/kg) with the same effectiveness, concluding the hydrophilic molecules are involved in these pharmacological activities. The anti-diabetic activity observed in the mice CsAE (100 mg/kg) was found in the mice treated with the butanol fraction (CsBUT, 100 mg/kg) not correlated with the hypolipidemic activity found in dichloromethane fraction (CsDC, 100 mg/kg). This finding suggests that these two activities are due to lipophilic molecules. Finally for the two plants, the activity on the weight is found in the whole of the fractions, which shows that this activity is due to molecules of different polarity. © 2017 Lavoisier
Roix J.J.,Biomedical Valley Discoveries Inc. |
Decrescenzo G.A.,Biomedical Valley Discoveries Inc. |
Cheung P.H.,Biomedical Valley Discoveries Inc. |
Ciallella J.R.,Melior Discovery, Inc. |
And 3 more authors.
Diabetes, Obesity and Metabolism | Year: 2012
Aims: To investigate the effects of the second generation antipsychotic (R/S)-amisulpride, and the chirally purified enantiomers, on glucose homeostasis in diet-induced obese (DIO) mice. Methods: Normal and DIO mice were treated with pharmacologically relevant doses of amisulpride prior to oral glucose tolerance tests (OGTTs). Blood glucose, insulin, glucagon-like peptide-1, prolactin and amisulpride drug levels were determined. Results: Racemic amisulpride significantly reduced glucose excursions during OGTT in both normal and DIO mice. This potent effect was preserved with the 'off-isomer', R-amisulpride (ED50 1 mg/kg). Insulin secretion was significantly increased with R-amisulpride with only a minor increase in prolactin levels. Conclusions: Amisulpride has antidiabetic actions in DIO mice resulting from increased insulin secretion. This provides some explanation for why amisulpride, unlike other atypical antipsychotics, is not diabetogenic in man. Furthermore, the observation that R-amisulpride is also antidiabetic and has minimal impact on prolactin levels presents the opportunity for development of this isomer as an antidiabetic agent. © 2011 Blackwell Publishing Ltd.
Castro-Perez J.,Merck And Co. |
Castro-Perez J.,Netherlands Metabolomics Center |
Briand F.,Physiogenex |
Gagen K.,Merck And Co. |
And 12 more authors.
Journal of Lipid Research | Year: 2011
Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol (HDL-C) and lowers LDL cholesterol in dyslipidemic patients; however, the effects of ANA on cholesterol/lipoprotein metabolism in a dyslipidemic hamster model have not been demonstrated. To test whether ANA (60mg/kg/day, 2 weeks) promoted reverse cholesterol transport (RCT), 3H-cholesterol-loaded macrophages were injected and 3H-tracer levels were mea sured in HDL, liver, and feces. Compared to controls, ANA inhibited CETP (94%) and increased HDL-C (47%). 3H-tracer in HDL increased by 69% in hamsters treated with ANA, suggesting increased cholesterol effl ux from macrophages to HDL. 3H-tracer in fecal cholesterol and bile acids increased by 90% and 57%, respectively, indicating increased macrophage-to-feces RCT. Mass spectrometry analysis of HDL from ANA-treated hamsters revealed an increase in free unlabeled cholesterol and CE. Furthermore, bulk cholesterol and cholic acid were increased in feces from ANA-treated hamsters. Using two independent approaches to assess cholesterol metabolism, the current study demonstrates that CETP inhibition with ANA promotes macrophageto- feces RCT and results in increased fecal cholesterol/bile acid excretion, further supporting its development as a novel lipid therapy for the treatment of dyslipidemia and atherosclerotic vascular disease. Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc.
Girousse A.,French Institute of Health and Medical Research |
Girousse A.,University Paul Sabatier |
Tavernier G.,French Institute of Health and Medical Research |
Tavernier G.,University Paul Sabatier |
And 53 more authors.
PLoS Biology | Year: 2013
When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity. © 2013 Girousse et al.