P465L‐PPARγ mutation confers partial resistance to the hypolipidaemic action of fibrates

内科学 内分泌学 胰岛素抵抗 极低密度脂蛋白 脂肪变性 脂肪肝 病理生理学 贝扎纤维 生物 突变体 脂蛋白 基因 医学 胰岛素 胆固醇 生物化学 疾病
作者
Sergio Rodríguez‐Cuenca,Stefania Carobbio,Gwendolyn Barceló‐Coblijn,Xavier Prieur,Joana Relat,Ramon Amat,Mark Campbell,Ana Dias,Myriam Bahri,Sarah L. Gray,Antonio Vidal–Puig
出处
期刊:Diabetes, Obesity and Metabolism [Wiley]
卷期号:20 (10): 2339-2350 被引量:3
标识
DOI:10.1111/dom.13370
摘要

Aims Familial partial lipodystrophic syndrome 3 (FPLD3) is associated with mutations in the transcription factor PPARγ. One of these mutations, the P467L, confers a dominant negative effect. We and others have previously investigated the pathophysiology associated with this mutation using a humanized mouse model that recapitulates most of the clinical symptoms observed in patients who have been phenotyped under different experimental conditions. One of the key clinical manifestations observed, both in humans and mouse models, is the ectopic accumulation of fat in the liver. With this study we aim to dissect the molecular mechanisms that contribute to the excessive accumulation of lipids in the liver and characterize the negative effect of this PPARγ mutation on the activity of PPARα in vivo when activated by fibrates. Material and Methods P465L‐PPAR mutant and wild‐type mice were divided into 8 experimental groups, 4 different conditions per genotype. Briefly, mice were fed a chow diet or a high‐fat diet (HFD 45% Kcal from fat) for a period of 28 days and treated with WY14643 or vehicle for five days before culling. At the end of the experiment, tissues and plasma were collected. We performed extensive gene expression, fatty acid composition and histological analysis in the livers. The serum collected was used to measure several metabolites and to perform basic lipoprotein profile. Results P465L mice showed increased levels of insulin and free fatty acids (FFA) as well as increased liver steatosis. They also exhibit decreased levels of very low density lipoproteins (VLDL) when fed an HFD. We also provide evidence of impaired expression of a number of well‐established PPARα target genes in the P465L mutant livers. Conclusion Our data demonstrate that P465L confers partial resistance to the hypolipidemic action of fibrates. These results show that the fatty liver phenotype observed in P465L mutant mice is not only the consequence of dysfunctional adipose tissue, but also involves defective liver metabolism. All in all, the deleterious effects of P465L‐PPARγ mutation may be magnified by their collateral negative effect on PPARα function.
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