Berberine Ameliorates Abnormal Lipid Metabolism via the Adenosine Monophosphate-Activated Protein Kinase/Sirtuin 1 Pathway in Alcohol-Related Liver Disease

Abstract

Alcoholic fatty liver disease (AFLD) is an early stage of alcohol-related liver disease characterized by abnormal lipid metabolism in hepatocytes. To date, to our knowledge, there have been no effective strategies for preventing or treating alcohol-related liver disease besides alcohol abstinence. Berberine (BBR) is the main bioactive ingredient extracted from traditional Chinese medicines, such as Coptis and Scutellaria, which protect liver function and relieve liver steatosis. However, the potential role of BBR in AFLD remains unclear. Therefore, this study investigated the protective effects of BBR against Gao-binge model-induced AFLD in 6- to 8-week-old C57BL/6J male mice in vivo and ethyl alcohol (EtOH)-induced alpha mouse liver 12 (AML-12) cells in vitro. The results showed that BBR (200 mg/kg) attenuated alcoholic liver injury and suppressed lipid accumulation and metabolism disorders in vivo. Consistently, BBR effectively inhibited the expression of sterol regulatory element-binding transcription factor 1C, sterol regulatory element-binding transcription factor 2, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoenzymeA reductase in EtOH-stimulated AML-12 cells in vitro and promoted the expression of sirtuin 1 (SIRT1) in EtOH-fed mice and EtOH-treated AML-12 cells. Furthermore, SIRT1 silencing attenuated the hepatic steatosis alleviation potential of BBR treatment. Mechanistically, molecular docking revealed the binding effect of BBR and adenosine monophosphate-activated protein kinase (AMPK). The results of further studies showed that a decrease in AMPK activity was accompanied by a significant inhibition of SIRT1 expression. SIRT1 silencing attenuated the protective effect of BBR, whereas the inhibition of its expression had no apparent effect on AMPK phosphorylation, suggesting that SIRT1 acts downstream of AMPK in AFLD. Collectively, BBR ameliorated abnormal lipid metabolism and alleviated EtOH-induced liver injury via the AMPK/SIRT1 pathway in AFLD mice.

Keywords: adenosine monophosphate–activated protein kinase; alcoholic fatty liver disease; berberine; lipid metabolism; sirtuin 1.