Docosahexaenoic acid (DHA; C22; n-3) shows beneficial effects on Non-alcoholic fatty liver disease (NAFLD). Deacetylase Sirtuin1 (Sirt1) was reported to increase energy metabolism and decrease lipogenesis. Here, we investigated whether DHA plays a role in protecting against hepatic steatosis via Sirt1. Main Methods: Both in vivo and in vitro hepatic steatosis models were used: diet-induced obesity (DIO) model (middle-aged C57BL/6 mice fed a high-fat diet (HFD)) and palmitic acid (PA)-induced lipid accumulation cell model (HepG2 cells). Key Findings: In DIO mice, treatment with DHA (gavage supplementation) for 8 weeks not only inhibited the lipid accumulation, but also increased fatty acids (FA) oxidation and induced triglyceride export in liver. These changes were accompanied by attenuation of inflammation. Moreover, DHA reversed the HFD-induced reduction of Sirt1 in liver. Interestingly, the beneficial effects of DHA were reversed by lentivirus-mediated Sirt1 knockdown, accompanied with increased expression of markers of lipogenesis, inflammation and reduced FA oxidation. In HepG2 cells, DHA prevented the accumulation of PA-induced lipid droplets, the decrease of FA oxidation and the reduction of Sirt1 level. Inhibition of Sirt1 by sirtinol partially reversed the beneficial effects of DHA on PA-treated cells. Significance: DHA alleviated hepatic steatosis and reduced inflammation of liver in obese middle-aged mice by mechanisms involving Sirt1 activation.

increasing prevalence of obesity-induced non-alcoholic fatty liver disease (naFld) and non-alcoholic steatohepatitis (naSH) has been reported. ascorbic acid (aa), also known as vitamin c, an excellent antioxidant, has been shown to exert beneficial effects on NAFLD; however, the underlying mechanisms are yet to be fully elucidated. in the present study, the role of aa on cell stress in tumor necrosis factor α (TnFα)-treated HepG2 cells was investigated. our findings revealed that exposure to AA effectively ameliorated TnFα-induced cell stresses, including hypoxia, inflammation and endoplasmic reticulum (er) stress by reducing the expression of Hif1α and its target genes (glucose transporter 1), pro-inflammatory genes (monocyte chemoattractant 1) and ER stress-related genes (glucose-regulated protein, 78 kda). aa also decreased the protein level of HiF1α. additionally, aa significantly increased the secretion of total adiponectin and high molecular weight (HMW) adiponectin. Mechanistically, AA was determined to increase the expression of fibroblast growth factor 21 (FGF21) and its receptor, fibroblast growth factor receptor 2 (FGFr2). Knockdown of FGFr2 not only decreased the levels of total adiponectin and HMW adiponectin, but almost abolished the beneficial effects of AA in ameliorating cell stress. Collectively, the findings of our study demonstrated that aa may attenuate hepatocyte stress induced by TnFα via activation of the FGF21/FGFr2/adiponectin pathway. This could a novel mechanism of action of aa, and its potential for the treatment of naFld/naSH.

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