AUTHOR=Xu Jia , He Xiaoyun , Huang Xianghui , Zhang Feng , Ren Xinxin , Asakiya Charles , Li Yue , Huang Kunlun 

TITLE=Artemether Ameliorates Non-Alcoholic Steatohepatitis by Repressing Lipogenesis, Inflammation, and Fibrosis in Mice

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.851342

DOI=10.3389/fphar.2022.851342

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Non-alcoholic fatty liver disease (NAFLD) is a widespread disease, but no recognized drug treatment exists. Previous studies have shown that artemether (Art) can ameliorate carbon tetrachloride (CCl<sub>4</sub>)–induced liver fibrosis in mice. This study sets out to observe the therapeutic impact of Art on non-alcoholic steatohepatitis (NASH).</p><p><bold>Methods:</bold> Model mice were provided with a methionine- and choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 28 weeks, respectively, and then treated with Art. RNA sequencing (RNA-Seq) analyzed gene expression changes caused by Art treatment. The molecular mechanism of the therapeutic effects of Art on NASH was studied in the mouse liver and HepG2 cells.</p><p><bold>Results:</bold> Art treatment significantly attenuated hepatic lipid accumulation and liver damage in MCD diet– or HFD-induced NASH mice. The RNA-Seq analysis revealed lipid metabolism as a major pathway suppressed by Art administration, in addition to the regulation of inflammation pathways. Mechanistically, Art reduced lipid accumulation by repressing <italic>de novo</italic> lipogenesis of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD1), promoting lipolysis of peroxisome proliferator–activated receptor-γ co-activator-1α (PGC1α), adipose triglyceride lipase (ATGL), and carnitine palmitoyltransferase I (CPT-1a) in NASH mouse liver and HepG2 cells. In addition, Art inhibited the secretion of pro-inflammatory factors and reduced inflammatory infiltration by effectively inhibiting M1 macrophage activation. Furthermore, Art inhibited transforming growth factor-beta 1 (TGF-β), and the SMAD signaling pathway mediates the development of liver fibrosis.</p><p><bold>Inclusion</bold>: Art improved fat deposition by repressing <italic>de novo</italic> lipogenesis and promoting lipolysis <italic>in vivo</italic> and <italic>in vitro</italic>. Furthermore, Art improved inflammation and fibrosis with a significant effect. It is a prospective therapeutic agent for NASH.</p>