Dihydroartemisinin attenuates alcoholic fatty liver through regulation of lipin-1 signaling.

Abstract

Alcoholic liver disease (ALD) is generated from excessive alcohol consumption, characterized by hepatic steatosis. Mechanistically, excessive hepatic lipid accumulation was attributed to the aberrant lipin-1 signaling during the development of alcoholic steatosis in rodent species and human. Dihydroartemisinin (DHA) has been recently identified to relieve hepatocytes necrosis and prevent from hepatic steatosis in alcohol-induced liver diseases; however, the role of DHA in ALD has not been elucidated completely. Therefore, this study was aimed to further identify the potential mechanisms of pharmacological effects of DHA on ALD. Results demonstrated that DHA regulated the expression and nucleocytoplasmic shuttling of lipin-1 in mice with chronic ethanol exposure. Results confirmed that the disruption of lipin-1 signaling abolished the suppression of DHA on alcohol-induced hepatic steatosis. Interestingly, DHA also significantly improved liver injury, and inflammation mediated by lipin-1 signaling in chronic alcohol-fed mice. in vivo experiments further consolidated the concept that DHA protected against hepatocyte lipoapoptosis dependent on the regulation of nucleocytoplasmic shuttling of lipin-1 signaling, resulting in attenuated ratio of Lpin1 β/α. Obvious increases in cell apoptosis were observed in alcohol-treated lipin1β-overexpressed mice. Although DHA attenuated cell apoptosis, overexpression of lipin-1β neutralized DHA action. DHA ameliorated activation of endoplasmic reticulum stress through inhibiting activation of JNK and CHOP, which was abrogated by overexpression of lipin-1β. In summary, DHA significantly improved liver injury, steatosis and hepatocyte lipoapoptosis in chronic alcohol-fed mice via regulation of lipin-1 signaling.

• Authors: Xingran Chen, Mianli Bian, Huanhuan Jin, Naqi Lian, Jiangjuan Shao, Feng Zhang, Shizhong Zheng
• Journal: IUBMB life (IUBMB Life) Vol. 71 Issue 11 Pg. 1740-1750 (11 2019) ISSN: 1521-6551 [Electronic] England
• PMID: 31265202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 International Union of Biochemistry and Molecular Biology.

Chemical References

• Antimalarials
• Artemisinins
• artenimol
• Lpin1 protein, mouse
• Phosphatidate Phosphatase

Topics

• Animals
• Antimalarials (pharmacology)
• Apoptosis (drug effects)
• Artemisinins (pharmacology)
• Cells, Cultured
• Endoplasmic Reticulum Stress (drug effects)
• Fatty Liver, Alcoholic (metabolism, pathology, prevention & control)
• Gene Expression Regulation (drug effects)
• Hepatocytes (drug effects, metabolism, pathology)
• Lipid Metabolism (drug effects)
• Male
• Mice
• Mice, Inbred ICR
• Phosphatidate Phosphatase (genetics, metabolism)
• Signal Transduction (drug effects)