Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes

Abstract

Background and PurposeThiazolidinediones, acting as PPAR‐γ ligands, reduce hepatic steatosis in humans and animals. However, the underlying mechanism of this action remains unclear. The purpose of this study was to investigate changes in hepatic metabolites and lipids in response to treatment with the thiazolidinedione pioglitazone in an animal model of obese Type 2 diabetes.Experimental ApproachMale Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were orally administered either vehicle (control) or pioglitazone (30 mg·kg−1) and fed a high‐fat diet (60% kcal fat) for 12 weeks. Hepatic metabolites were analysed via metabolomic and lipidomic analyses. Gene expression and PLA2 activity were analysed in livers from pioglitazone‐treated and control rats.Key ResultsOLETF rats that received pioglitazone showed decreased fat accumulation and improvement of lipid profiles in the liver compared to control rats. Pioglitazone treatment significantly altered levels of hepatic metabolites, including free fatty acids, lysophosphatidylcholines and phosphatidylcholines, in the liver. In addition, pioglitazone significantly reduced the expression of genes involved in hepatic de novo lipogenesis and fatty acid uptake and transport, whereas genes related to fatty acid oxidation were up‐regulated. Gene expression and enzyme activity of PLA2, which hydrolyzes phosphatidylcholines to release lysophosphatidylcholines and free fatty acids, were significantly decreased in the livers of pioglitazone‐treated rats compared to control rats.Conclusions and ImplicationsOur results present evidence for the ameliorative effect of pioglitazone on hepatic steatosis, largely due to the regulation of lipid metabolism, including fatty acids, lysophosphatidylcholines, phosphatidylcholines and related gene‐expression patterns.

The anti-obesity effect of lotus leaves on high-fat-diet-induced obesity by modulating lipid metabolism in C57BL/6J mice

“…LPL also participates in converting apolipoproteins and phospholipids between VLDL and HDL, thus increasing HDL-C levels [42]. These two lipases are target genes regulated by PPAR-α and PPAR-γ [43][44][45]. CYP7A1 is a rate-limiting enzyme that catalyzes bile acid synthesis by cholesterol, which is important for maintaining the internal balance of bile acids [46].…”

Malus hupehensis leaves extract attenuates obesity, inflammation, and dyslipidemia by modulating lipid metabolism and oxidative stress in high‐fat diet‐induced obese mice

“…It regulates lipid metabolism-related target genes to promote fatty acid oxidation, ketogenesis, fatty acid uptake, and triglyceride metabolism to reduce lipid accumulation (Gross et al, 2017;Ma et al, 2011). PPARs signaling pathway (Niu et al, 2010;Shah et al, 2010;Yang et al, 2018). CYP7A1 is also a rate-limiting enzyme.…”

“…LPL and CPT1 genes are downstream targets of PPAR‐γ and PPAR‐α. Their expression level is regulated by PPAR‐γ and PPAR‐α to control lipid metabolism and lipid deposition via PPARs signaling pathway (Niu et al., 2010; Shah et al., 2010; Yang et al., 2018). CYP7A1 is also a rate‐limiting enzyme.…”

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“…Metabolomics represent a valuable approach for studying the pathophysiology of diverse disease states, including obesity 15 , DM 16 , and diabetic retinopathy 13 by revealing differences in metabolic pathways according to disease status, and enabling the discovery of novel biomarkers for anticipating dysfunction and disease.…”