Arrestin domain containing 3 promotes alcohol-induced liver steatosis by reducing stearoyl-CoA desaturase-1 ubiquitinated degradation

Background and aims

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide with no approved therapy. The development of ALD is strongly associated with hepatic lipid accumulation. Arrestin domain containing 3 (ARRDC3), a member of the α-arrestin family, is involved in obesity, inflammation, and cancer. However, its role in ALD remains largely unexplored.

Methods

Both the NIAAA and traditional Lieber-De Carli mouse models of ALD were employed. ARRDC3 expression was evaluated in liver specimens from ALD patients, mouse hepatic tissues, and hepatocytes. Hepatocyte-targeted Arrdc3 knockdown was achieved through intrahepatic delivery of adeno-associated virus 8 (AAV8) carrying shRNA under a hepatocyte-specific promoter. Mass spectrometry analysis, immunofluorescence, co-immunoprecipitation (co-IP) assays, and molecular docking were used to identify the interaction between ARRDC3 and stearoyl-CoA desaturase 1 (SCD1).

Results

ARRDC3 levels were significantly elevated in the livers of both ALD patients and mouse models. Knockdown of Arrdc3 using AAV8 alleviated alcohol-induced liver steatosis in both the NIAAA and traditional Lieber-De Carli mouse models. We demonstrated that ARRDC3 promoted the progression of ALD by inducing lipid accumulation in hepatocytes. Mechanistically, ARRDC3 directly binds to SCD1 and inhibits its ubiquitin-proteasome degradation. Inhibition of SCD1 blocked ARRDC3-induced lipid deposition in hepatocytes. We also observed a correlation between ARRDC3 and SCD1 in liver samples from ALD patients.

Conclusions

Our findings reveal that ARRDC3 promotes hepatic steatosis in ALD by reducing the ubiquitin-dependent degradation of SCD1. ARRDC3 may serve as a potential therapeutic target for ALD.