Resolution of nonalcoholic fatty liver and nonalcoholic steatohepatitis by a novel adipokine

Project Summary Nonalcoholic steatohepatitis (NASH) is initiated by lipid accumulation in hepatocytes and further characterized by lobular inflammation, hepatocyte ballooning, and varying degrees of fibrosis that can lead to cirrhosis, liver failure and cancer. Despite its high prevalence and clinical importance, there are currently no approved therapies. As steatosis is a key driver for the pathogenesis of NASH, there is clearly a need to identify novel signaling molecules and pathways regulating hepatic lipid metabolism and evaluate their therapeutic potential in NASH animal models. We identified an adipose-enriched adipokine. our preliminary data show that recombinant protein of this adipokine induces gene expression program of mitochondrial biogenesis and fatty acid oxidation and represses program of de novo lipogenesis in the liver, leading to a rapid and robust resolution of liver steatosis and NASH. In Aim 1, we will investigate whether this adipokine will resolve NASH and other metabolic comorbidities in two NASH mouse models. In Aim 2, we will investigate the in vivo mechanism underlying the resolution of NASH by this adipokine. In Aim 3, we will identify the receptor targeted by this adipokine and perform global phosphoproteomic studies.