Pterostilbene and Its Derivative 3′-Hydroxypterostilbene Ameliorated Nonalcoholic Fatty Liver Disease Through Synergistic Modulation of the Gut Microbiota and SIRT1/AMPK Signaling Pathway

Nonalcoholic fatty liver disease (NAFLD) is a recent chronic liver disease common in many developed countries and is closely associated with metabolic syndrome, such as obesity and insulin resistance. The present study was performed to investigate the effects of pterostilbene (Pt) and its derivative 3'-hydroxypterostilbene (OHPt) on free fatty acids (FFA)-induced lipid accumulation in HepG2 cells and high-fat diet (HFD)-induced NAFLD in C57BL/6J mice. The results showed that Pt and OHPt significantly ameliorated FFA-induced steatosis in HepG2 cells and enhanced lipolysis through the upregulation of SIRT1/AMPK and insulin signaling pathways. In the in vivo study, Pt and OHPt treatment resulted in reduced hepatic lipid droplets accumulation. The data showed that Pt and OHPt upregulated the SIRT1/AMPK pathway and subsequently downregulated the protein expression of SREBP-1 to activate fatty acid (FA) β-oxidation to inhibit FA synthesis. Pt and OHPt administration activated the insulin signaling pathway and further ameliorated the insulin resistance and liver function in the HFD-fed mice. Furthermore, Pt and OHPt markedly increased the numbers of Oscillospira and decreased the numbers of Allobaculum, Phascolarctobacterium, and Staphylococcus compared with those in the HFD group. These robust results indicate that Pt and OHPt are able to possess potential health benefits in improving insulin resistance and hepatic steatosis by promoting healthy populations or abundances of considered vital microbiota. Besides, OHPt is more effective than Pt, which might have promising chemotherapeutic effects for future clinical application.