ARRB1 Inhibits The Progression Of Non-alcoholic Steatohepatitis By Promoting The Maturation Of GDF15

Non-alcoholic fatty liver disease(NAFLD)in general encompasses a clinical spectrum ranging from simple steatosis and non-alcoholic steatohepatitis(NASH)to cirrhosis and even hepatocellular carcinoma(HCC).NASH is associated with dysregulation of lipid metabolism and hepatic inflammation.Triglycerides and other lipids accumulation in the liver acts as the primary insult which initiates and propagates damage leading to hepatocellular injury and resultant infiltration of inflammatory cells.NASH is also described as the hepatic correlate of the metabolic syndrome and is thereby in most instances associated with insulin resistance,obesity,type 2 diabetes or dyslipidemia.The causal mechanism underlying NASH is not fully elucidated.We dedicate to investigate the role of β-arrestin1(ARRB1)in the progression of NASH.ARRB1,originally identified as a negative regulator of G protein-coupled receptor signaling,has been demonstrated to function as molecular scaffold that regulates cellular function by interacting with other partner proteins,and to be involve in multiple physiological process including immune response,tumorigenesis and inflammation.Emerging evidence has indicated that treatment or overexpression of GDF15 decreases the body weight and improves metabolic profiles in mice and monkeys.Moreover,recent studies reveal that GDF15 promotes fatty acid β-oxidation,decreases adiposity and corrects the metabolic dysfunction in mice fed with HFD.Here,we have shown that ARRB1 expression was diminished in NASH patient liver samples.Moreover,diminished ARRB1 levels were detected in mice NASH models.ARRB1 deficiency accelerated steatohepatitis development in HFD-/MCD diet-fed mice accompanied by upregulation of lipogenic genes and downregulation ofβ-oxidative genes.Intriguingly,ARRB1 was found to interact with GDF15 and facilitated the transportation of GDF15 precursor(pro-GDF15)to Golgi apparatus for cleavage and maturation.Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of ARRB1 deletion in vitro and in vivo.Re-expression of ARRB1 in the NASH models ameliorated the liver disease,and the effect was greater in the presence of pro-GDF15 overexpression.In contrast,the effect of proGDF15 overexpression alone was impaired in ARRB1-deficient mice.In addition,the severity of liver condition in patients with NASH was negatively correlated with ARRB1 expression.To sum up,ARRB1 acts as a vital regulator in the development of NASH via facilitating GDF15’s translocation to the Golgi apparatus and subsequent maturation.Thus,ARRB1 is a potential therapeutic target for the treatment of NASH.