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Objectives: Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high‐density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established. Methods: In this study, wild‐type and Ppara‐null mice fed a medium‐fat diet (MFD) were administered gemfibrozil and fenofibrate for 3 months respectively, to explore the effect and action mechanism. Key findings: In Ppara‐null mice, MFD treatment increased body weight, adipose tissue, serum TG and impaired glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild‐type group. In 3T3‐L1 adipogenic stem cells treated with high glucose, STAT3 knockdown greatly decreased the number of lipid droplets. Conclusions: Low dose of clinical fibrates was effective against MS development independent of PPARα, and this action was mediated by STAT3 signalling inhibition in adipose tissue and, to a lesser extent, in hepatic tissues. [ABSTRACT FROM AUTHOR]

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Highlights • In chronic cholestsis, bile acid metabolism adaptation is inhibited in wild-type mice but not in Ppara -null mice. • FXR pathway is activated in Ppara -null mice, not in wild-type mice. • Cross-talk between basal PPARα and FXR inhibit bile acid metabolism adaptation in chronic cholestasis. Abstract Cholestasis is one of the most challenging diseases to be treated in current hepatology. However little is known about the adaptation difference and the underlying mechanism between acute and chronic cholestasis. In this study, wild-type and Pparα -null mice were orally administered diet containing 0.05% ANIT to induce chronic cholestasis. Biochemistry, histopathology and serum metabolome analysis exhibited the similar toxic phenotype between wild-type and Pparα -null mice. Bile acid metabolism was strongly adapted in Pparα -null mice but not in wild-type mice. The Shp and Fxr mRNA was found to be doubled in cholestatic Pparα -null mice compared with the control group. Western blot confirmed the up-regulated expression of FXR in Pparα -null mice treated with ANIT. Inflammation was found to be stronger in Pparα -null mice than those in wild-type mice in chronic cholestasis. These data chain indicated that bile acid metabolism and inflammation signaling were different between wild-type and Pparα -null mice developing chronic cholestasis, although their toxic phenotypes could not be discriminated. So basal PPARα cross-talked with FXR and inhibited bile acid metabolism adaptation in chronic cholestasis. [ABSTRACT FROM AUTHOR]