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

Jia Xu; Xiaoyun He; Xianghui Huang; Feng Zhang; Xinxin Ren; Charles Asakiya; Yue Li; Kunlun Huang

doi:10.3389/fphar.2022.851342

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

Front Pharmacol. 2022 May 2:13:851342. doi: 10.3389/fphar.2022.851342. eCollection 2022.

Authors

Jia Xu¹, Xiaoyun He^{1

2}, Xianghui Huang¹, Feng Zhang¹, Xinxin Ren¹, Charles Asakiya¹, Yue Li³, Kunlun Huang^{1

2}

Affiliations

¹ Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.
² Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), The Ministry of Agriculture and Rural Affairs, Beijing, China.
³ Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.

Abstract

Background: 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 (CCl₄)-induced liver fibrosis in mice. This study sets out to observe the therapeutic impact of Art on non-alcoholic steatohepatitis (NASH). Methods: 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. Results: 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 de novo 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. Inclusion: Art improved fat deposition by repressing de novo lipogenesis and promoting lipolysis in vivo and in vitro. Furthermore, Art improved inflammation and fibrosis with a significant effect. It is a prospective therapeutic agent for NASH.

Keywords: artemether; inflammation; lipid metabolism; lipogenesis; liver fibrosis; non-alcoholic steatohepatitis.