Background and purpose: Silymarin, a standardized extract of the milk thistle seeds, has been widely used to treat chronic hepatitis, cirrhosis, and other types of toxic liver damage. Despite increasing studies on the action of silymarin and its major active constituent, silybin in their therapeutic properties against insulin resistance, diabetes and hyperlipidaemia in vitro and in vivo, the mechanism underlying silymarin action remains unclear.Experimental approach: C57BL/6 mice were fed high-fat diet (HFD) for 3 months to induce obesity, insulin resistance, hyperlipidaemia, and fatty liver. These mice were then continuously treated with HFD alone or mixed with silymarin at 40 mg/100 g for additional 6 weeks. Biochemical analysis was used to test the serum lipid and bile acid profiles. Farnesyl X receptor (FXR) and nuclear factor kappa B (NF-κB) transactivities were analyzed in liver using a gene reporter assay based on quantitative RT-PCR.Key results: Silymarin treatment ameliorated insulin resistance, dyslipidaemia and inflammation, and reconstituted the bile acid pool in liver of diet-induced obesity. Associated with this, silybin and silymarin enhanced FXR transactivity. Consistently, in HepG2 cells, silybin inhibited NF-κB signaling, which was enhanced by FXR activation.Conclusion and implications: Our results suggest that silybin is an effective component of silymarin for treating metabolic syndrome by stimulating FXR signaling.

Background and Purpose: The molecular mechanism for the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains elusive. Both farnesoid X receptor (FXR) signalling and endoplasmic reticulum (ER) stress contribute to the progression of NAFLD; however, it is not clear whether the actions of these two pathways are dependent on each other. Moreover, the pharmacological benefits and mechanism of betulinic acid (BA) in controlling metabolic syndrome and NAFLD are largely unknown.Experimental Approach: A reporter assay and a time-resolved FRET assay were used to identify BA as an agonist of the FXR. NAFLD was induced by a methionine and choline-deficient L-amino acid diet (MCD) and high-fat diet (HFD). The pharmacological effects of BA (100 mg·kg −1 ·day −1 ) and potential interactions between hepatic FXR activation and ER stress pathways were evaluated by FXR silencing, Western blot and RT-PCR analyses using control and FXR −/− mice.Key Results: Activation of the FXR inhibited intracellular PERK/EIF2α/ATF4 and CHOP signalling, thereby alleviating hepatic ER stress, whereas FXR silencing resulted in an opposite effect. Furthermore, we identified BA as an FXR agonist that effectively attenuated the progression of NAFLD and metabolic disorders in both HFD-and MCD diet-fed mice and restored the hepatocellular ER homeostasis by stimulating the FXR signalling pathway and blocking PERK/EIF2α signalling. In contrast, the effects of BA were attenuated in FXR −/− mice. Conclusions and Implications:Our data demonstrate that pharmacological activation of the FXR by BA reduces hepatocellular ER stress and attenuates NAFLD in an animal model of hepatic steatosis.

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