ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation

Abstract

Background & aims: Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. This study investigated the role of β-Arrestin1 (ARRB1) in the progression of NASH.

Methods: Liver tissue from patients with NASH and controls were obtained to evaluate ARRB1 expression. NASH models were established in Arrb1-knockout and wild-type mice fed either a high-fat diet (HFD) for 26 weeks or a methionine/choline-deficient (MCD) diet for 6 weeks.

Results: ARRB1 expression was reduced in liver samples from patients with NASH. Reduced Arrb1 levels were also detected in murine NASH models. Arrb1 deficiency accelerated steatohepatitis development in HFD-/MCD-fed mice (accompanied by the upregulation of lipogenic genes and downregulation of β-oxidative genes). Intriguingly, ARRB1 was found to interact with growth differentiation factor 15 (GDF15) and facilitated the transportation of GDF15 precursor (pro-GDF15) to the Golgi apparatus for cleavage and maturation. Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of Arrb1 deletion both in vitro and in vivo. Re-expression of Arrb1 in the NASH models ameliorated the liver disease, and this effect was greater in the presence of pro-GDF15 overexpression. By contrast, the effect of pro-GDF15 overexpression alone was impaired in Arrb1-deficient mice. In addition, the severity of liver disease in patients with NASH was negatively correlated with ARRB1 expression.

Conclusion: ARRB1 acts as a vital regulator in the development of NASH by facilitating the translocation of GDF15 to the Golgi apparatus and its subsequent maturation. Thus, ARRB1 is a potential therapeutic target for the treatment of NASH.

Lay summary: Non-alcoholic steatohepatitis (NASH) is associated with the progressive dysfunction of lipid metabolism and a consequent inflammatory response. Decreased ARRB1 is observed in patients with NASH and murine NASH models. Re-expression of Arrb1 in the murine NASH model ameliorated liver disease, an effect which was more pronounced in the presence of pro-GDF15 overexpression, highlighting a promising strategy for NASH therapy.

Keywords: ARRB1; GDF15; GFRAL; Inflammation; Metabolism; NAFLD; NASH; Non-alcoholic steatohepatitis.