Affiliation:
1. Department of Gastroenterology Xinhua Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
2. Shanghai Key Lab of Pediatric Gastroenterology and Nutrition Shanghai China
3. Department of Gastroenterology Ningbo No. 2 Hospital Ningbo Zhejiang Province China
Abstract
ObjectivesArtesunate (ART) is a water‐soluble derivative of artemisinin, which has shown anti‐inflammatory, anti‐tumor, and immunomodulating effects. We aimed to investigate the potential therapeutic effects and mechanisms of ART in metabolic dysfunction‐associated steatohepatitis (MASH).MethodsThe mice were randomly divided into the control group, high‐fat, high‐cholesterol diet‐induced MASH group, and the MASH treated with ART (30 mg/kg once daily) group. Liver enzymes, lipids, and histological features were compared among groups. The molecular mechanisms were studied by transcriptomic and lipidomics analyses of liver tissues.ResultsThe mice of the MASH group had significantly increased hepatic fat deposition and inflammation in terms of biochemical indicators and pathological manifestations than the control group. The ART‐treated group had improved plasma liver enzymes and hepatic cholesterol, especially at week 4 of intervention (p < 0.05). A total of 513 differentially expressed genes and 59 differentially expressed lipids were identified in the MASH group and the MASH+ART group. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment test showed that ART regulated glycerolipid metabolism pathway and enhanced fatty acid degradation. Peroxisome proliferator‐activated receptor (PPAR)‐α acted as a key transcription factor in the treatment of MASH with ART, which was confirmed by cell experiment.ConclusionsART significantly improved fat deposition and inflammatory manifestations in MASH mice, with potential therapeutic effects. The mechanism of artemisinin treatment for MASH may involve extensive regulation of downstream genes by upstream transcription factors, such as PPAR‐α, to restore hepatic lipid homeostasis.
Funder
National Natural Science Foundation of China