FXR overexpression restores NLRP3-mediated mitophagy and improves mitochondrial dysfunction in alcoholic liver disease.

Abstract

Alcoholic liver disease (ALD) is a common chronic liver disease worldwide, directly caused by excessive and prolonged alcohol consumption. To date, there are no acknowledged therapeutic approaches for treating ALD. The reason is that ALD pathogenesis is multifactorial and only partially understood. Mitochondrial dysfunction-related mitophagy and inflammation are essential factors that play critical roles in the pathogenesis and progression of ALD. The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays a well-established role in liver protection, but whether and how it counteracts ALD by regulating mitophagy remains unknown. This study aimed to demonstrate the protective effect of FXR overexpression against ethanol-induced liver injury by suppressing NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting mitophagy recovery. The mouse ALD models were established using the DeCarli liquid diet with 5% ethanol (v/v). We established FXR-overexpressing mice by intravenous injection of FXR-mediating lentivirus (LV-FXR). The results revealed that FXR expression was significantly downregulated in liver tissues of ALD patients compared to normal subjects using the Gene Expression Omnibus (GEO) database. FXR overexpression reduced the liver-to-body weight ratio and improved biochemical markers in mice. Overexpression of FXR in mice significantly alleviated ethanol-induced hepatitis, improved mitophagy, and inhibited NLRP3 inflammasome activation and the secretion of IL-18 and IL-1β. In vitro, we transfected AML-12 cells with either pcDNA-FXR or FXR siRNA plasmids before ethanol exposure. Overexpression of FXR markedly attenuated ethanol-induced mitochondrial damage and NLRP3 inflammasome activation. Conversely, FXR knockdown exacerbated both outcomes. In conclusion, FXR overexpression protects against ethanol-induced liver injury through a novel mechanism by suppressing mitochondrial damage, oxidative stress, and NLRP3 inflammasome activation.