These data suggest that the protective effects of fenofibrate against cholestasis-induced hepatic injury are dependent on PPARα and fenofibrate dose, and are mediated through inhibition of JNK signalling. This mechanism of fenofibrate protection against intrahepatic cholestasis may offer additional therapeutic opportunities for cholestatic liver diseases.

α-Naphthylisothiocyanate (ANIT) is an experimental agent used to induce intrahepatic cholestasis. The Ppara-null mouse line is widely employed to explore the physiological and pathological roles of PPARα. However, little is known about how PPARα influences the hepatotoxicity of ANIT. In the present study, wild-type and Ppara-null mice were orally treated with ANIT to induce cholestasis. The serum metabolome of wild-type mice segregated from that of the Ppara-null mice, driven by changes of bile acid (BA) metabolites. Alkaline phosphatase and total BAs were elevated preferentially in Ppara-null mice, which correlated with changes in Cyp7a1, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5 genes and showed cross-talk between basal PPARα and potentially adaptive pathways. Il6, Tnfa, and target genes in the STAT3 pathway ( Socs3, Fga, Fgb, and Fgg) were up-regulated in Ppara-null mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-κB and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPARα involves regulation of BA metabolism and inhibition of NF-κB/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPARα, caution should be exercised when one attempts to draw conclusions in which the PPARα is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies.

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 three months, to explore the effect and action mechanism. Key findings In Ppara-null mice, MFD treatment increased body weight, adipose tissue, serum TG, and impared 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 signaling inhibition in adipose tissue, and to a lesser extent in hepatic tissues.

α-naphthylisothiocyanate (aniT) is used to induce intrahepatic cholestasis and it is frequently used for investigations into the disease mechanism. The lithocholic acid (lca) cholestatic model has also been extensively used in various studies; however, to the best of our knowledge, a comparative study determining the hepatotoxic mechanisms induced by these two models has not been previously conducted. in the present study, icr mice were treated with aniT or lca to induce cholestatic liver injury. Biochemical analysis was used to determine the serum. alanine aminotransferase (alT), aspartate aminotransferase (aST), alkaline phosphatase (alP) and total bile acid (TBa) levels, and histopathological assessment was used to examine the liver tissue. Metabolomic analysis was used for the serum biomarker identification. reverse transcription-quantitative Pcr analysis and western blotting were used to analyze the inflammation biomarkers. The serum metabolome of the aniT group clustered away from of the lca group, which was demonstrated by the different modifications of the BA components. ALP level was found to be preferentially increased in the aniT group from 24 to 48 h. Total Ba levels was only increased in the aniT group at 24 h. in contrast, aST and alT activity levels were preferentially increased in the lca group. The bile ducts in the hepatic tissues of the aniT group were observed to be severely dilated, whereas the presence of edematous hepatocytes around the necrotic lesions and neutrophil infiltration were identified in the lca group. The expression levels of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase genes were significantly downregulated in the ANIT group compared with the lca group, where a stronger adaptation of Ba metabolism was supported by major differences in the concentration of the Ba components. despite the aforementioned etiological differences in the cholestasis induced by each treatment, the activation of the JnK/STaT3 signaling pathway was similar between the two cholestatic models. in conclusion, these data suggested that the liver injury induced by aniT may be cholestatic, while the liver injury caused in the lca model may be hepatocellular. Moreover, the downstream cholestatic liver injury in both models was indicated to be mediated by the JnK/STaT3 signaling pathway.

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