APOE3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome

Aims This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is simil...

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Published in:	Diabetes, obesity & metabolism Vol. 16; no. 6; pp. 537 - 544
Main Authors:	van den Hoek, A. M., van der Hoorn, J. W. A., Maas, A. C., van den Hoogen, R. M., van Nieuwkoop, A., Droog, S., Offerman, E. H., Pieterman, E. J., Havekes, L. M., Princen, H. M. G.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-06-2014 Wiley Subscription Services, Inc
Subjects:	11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors Animals Antidiabetics Apolipoprotein E Apolipoprotein E3 - genetics Atorvastatin Atorvastatin Calcium Cholesterol Cholesterol Ester Transfer Proteins - genetics Diabetes Diabetes mellitus diabetic dyslipidemia Disease Models, Animal Drugs Dyslipidemia Esters Fatty liver Fenofibrate Fenofibrate - pharmacology Glucagon-Like Peptide 1 - analogs & derivatives Glucagon-Like Peptide 1 - pharmacology Heptanoic Acids - pharmacology High density lipoprotein Humans Hypoglycemic Agents - pharmacology Hypolipidemic Agents - pharmacology insulin resistance Lipids Liraglutide Liver diseases Male Metabolic disorders Metabolic syndrome Metabolic Syndrome - drug therapy Metabolic Syndrome - genetics Mice, Transgenic NAFLD Niacin - pharmacology Nicotinic acid Non-alcoholic Fatty Liver Disease - drug therapy Non-alcoholic Fatty Liver Disease - genetics obesity Obesity - drug therapy Obesity - genetics pharmacological treatment Pyrroles - pharmacology Rosiglitazone Thiazolidinediones - pharmacology Transgenic mice Triglycerides Vitamin B NAFLD pharmacological treatment insulin resistance obesity diabetic dyslipidemia
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Summary:	Aims This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. Methods Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11β‐hydroxysteroid‐dehydrogenase‐1 (HSD‐1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4–6 weeks. The effects on bw, IR and plasma and liver lipids were assessed. Results Rosiglitazone, liraglutide and HSD‐1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD‐1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high‐density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin. Conclusions We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non‐alcoholic fatty liver disease (NAFLD).
Bibliography:	ArticleID:DOM12252 Figure S1. Study scheme.Figure S2. Lipoprotein profiles of APOE3Leiden.humanCholesteryl Ester Transfer Protein (APOE3Leiden.CETP) mice on a high-fat diet before (t = 16 weeks) and after (t = 20 weeks) adding 10% fructose to the drinking water and of APOE3Leiden.CETP mice on a chow diet before (t = 0 weeks) and at the end of the experiment (age-matched control mice). The distribution of cholesterol over the individual lipoprotein profiles in pooled plasma was determined after separation of lipoprotein profiles by fast-performance liquid chromatography (FPLC).Figure S3. Lipoprotein profiles of diet induced obese APOE3Leiden.humanCholesteryl Ester Transfer Protein (APOE3Leiden.CETP) mice treated with different antidiabetic drugs: low and high dose of rosiglitazone (A) and liraglutide or 11β-hydroxysteroid-dehydrogenase-1 (HSD-1) inhibitor (B) or different hypolipidemic drugs: atorvastatin or fenofibrate (C) or low and high dose of niacin (D) and for 4 weeks. The distribution of cholesterol over the individual lipoprotein profiles in pooled plasma was determined after separation of lipoprotein profiles by fast-performance liquid chromatography (FPLC).Figure S4. Representative photographs of haematoxylin-phloxine-saffron stained liver sections of APOE3Leiden.humanCholesteryl Ester Transfer Protein (APOE3Leiden.CETP) mice on a chow diet, a high-fat diet or high-fat diet induced obese mice treated with either rosiglitazone 11 mg/kg/day, liraglutide 0.2 mg/kg/day or atorvastatin 10 mg/kg/day. Magnification: ×200. The biochemical data from analysis of hepatic lipids were confirmed by the histopathological analysis, as reflected by the clear decrease in vacuolization and hypertrophy in the rosiglitazone- and liraglutide-treated group, and to a lesser extent in the atorvastatin treated group, as compared with the control-HFD group.Table S1. Induction of obesity, insulin resistance and dyslipidemia in APOE3Leiden.humanCholesteryl Ester Transfer Protein (APOE3Leiden.CETP) mice.Appendix S1. Background of the APOE3Leiden mouse and additional methods. istex:C4E1A16E9C8F7541353AEAE0ED6E6E3FF6598211 ark:/67375/WNG-0P07XZKM-M ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1462-8902 1463-1326
DOI:	10.1111/dom.12252