Since non-alcoholic fatty liver disease (NAFLD) is being recognized as a primary cause of hepatitis and liver fibrosis/cirrhosis and increases worldwide, the development of effective anti-fatty liver drugs is clinically required. NAFLD is manifested by the excessive lipid accumulation in hepatocytes and sterol regulatory element-binding protein (SREBP)-1c plays an important role in de novo hepatic fatty acid synthesis. Endoplasmic reticulum (ER) stress can regulate the expression and activity of SREBP-1c, thus contributing to the pathogenesis of NAFLD. In the present study, we investigated the effects of 1-hydroxy-2-naphthoic acid (1-HNA), a novel chemical chaperone identified in high throughput screening (HTS) on the hepatic de novo lipogenesis in in vitro and in vivo mouse models. Pretreatment of 1- HNA reduced the protein expression of SREBP-1c enhanced by tunicamycin, an ER stress inducer in HepG2 cells in a concentration-dependent manner. Interestingly, 1-HNA also inhibited SREBP-1c expression induced by either insulin or a synthetic LXRα ligand (T0901317). We further investigated the inhibitory effects of 1-HNA in C57BL/6 mice fed high-fat diet (HFD) for 7 weeks. Oil Red O and H & E stainings showed that lipid accumulation in the liver were markedly reduced in the group orally treated with 1-HNA. Moreover, fasting blood glucose and serum total cholesterol levels were decreased by 1-HNA treatment. The ER stress marker proteins including CHOP and p-PERK were also reduced. To identify the underlying mechanism, we focused on the mTOR-p70S6K signaling which can regulate LXRα-SREBP-1c pathway. Rapamycin, an mTOR inhibitor suppressed tunicamycin-induced SREBP-1c expression. Surprisingly, 1-HNA blocked the mTOR/p70S6K signaling pathway activated by either tunicamycin or insulin and similarly, mTOR/p70S6K pathway was attenuated in HFD plus 1-HNA treated group compared to HFD alone. These inhibitory effects of 1-HNA explain, at least partly, its anti-fatty liver effects. Finally, our results suggest the potential of 1-HNA as a promising candidate for the treatment of NAFLD.

Anti-fatty liver effects of 1-Hydroxy-2-naphthoic acid, a novel chemical chaperone

2019 Fall National Meeting

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