A novel arctigenin derivative attenuates nonalcoholic fatty liver disease by activating adiponectin receptor 1-mediated AMPK signaling pathway.

Nonalcoholic fatty liver disease (NAFLD), along with metabolic syndrome and obesity, has seen a dramatic rise in frequency around the world. Arctigenin (ATG) has better efficacy in the treatment of non-alcoholic fatty liver in vitro, but its application in vivo models is limited due to its low oral bioavailability and poor water solubility. Compound ARC-18 is a derivative of ATG. As a prodrug, it improves the bioavailability and solubility of ATG, so that ARC-18 can also have better pharmacological activity in oral administration. The main purpose of this article is to explore the therapeutic effect of compound ARC-18 in nonalcoholic steatohepatitis and its possible mechanism. C57BL/6 J mice were fed with methionine and choline deficient (MCD) diet for 8 weeks to induce NAFLD and were given ARC-18 by gavage for 6 weeks (Proteomics Analysis and Histopathological analysis). The effect of ARC-18 was also investigated in AML12 cells exposed to palmitic acid. Our study showed that ARC-18 (33.0 mg/kg body weight) improved hepatic lipid accumulation, inflammatory damage and liver fibrosis in MCD diet feeding mice. Proteomic analyses indicated that ARC-18 exerts beneficial effects on inflammation, oxidative stress, and lipid metabolism. ARC-18 decreased lipid accumulation and promoted lipid oxidation by activating adiponectin receptor 1 (Adipo1 receptor) -mediated Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in vivo and vitro. Our data implies that ARC-18 is a therapeutic medication for the treatment of NAFLD, and that this protective effect is achieved by activating the hepatic Adipo1 receptor-mediated AMPK signaling pathway.