Role of the ubiquitin E3 ligase HUWE1 in age-associated nonalcoholic fatty liver disease

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Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide and is estimated to affect nearly 30% of the population. Rather than a single disorder, NAFLD refers to a spectrum of conditions that are characterized by excessive fat accumulation in the liver (hepatic steatosis) that occurs independently of excessive alcohol ingestion. With increased hepatocyte injury and inflammation, hepatic steatosis can progress to nonalcoholic steatohepatitis (NASH), followed by cirrhosis and fibrosis which lead to increased risk for developing hepatocellular carcinoma (HCC). Although hepatic steatosis can be reversed in early NAFLD with weight loss, diet, and exercise, liver damage resulting from inflammation, cirrhosis, and fibrosis observed in advanced NAFLD is often deemed irreversible. Therefore, there is a critical need to identify molecular mechanisms contributing to NALFD etiology and progression to identify therapeutic targets before the disease becomes clinically unmanageable. While several factors are known to contribute to the onset and progression of NAFLD-related disorders, aging is one of the highest risk factors. However, the mechanism underlying age- associated NAFLD remain incompletely understood. HUWE1 is a HECT-domain ubiquitin E3 ligase ubiquitously expressed in normal tissues. HUWE1 ubiquitinates a wide range of cellular substrates, including p53, MYC, and MCL1. Given the diverse substrates, the in vivo role of HUWE1 in human disease remains elusive. We have recently identified that HUWE1 is a critical mediator of NAFLD etiology as liver-specific Huwe1 knockout rendered mice protected against hepatic steatosis induced by age. Our novel data suggest that dysregulation of hepatic HUWE1 may play an important role in the pathogenesis of age-associated NAFLD. To test this hypothesis, we will identify the mechanism of how HUWE1 promotes age-associated NAFLD (Aim 1) and identify the substrate of HUWE1 that prevents the disease in mice (Aim 2). The successful completion of the proposed study will establish HUWE1 as a key regulator of age-associated NAFLD. This outcome will have a durable impact in the field since it will uncover a signaling pathway previously unrecognized and provide a rationale for investigating the mechanism of HUWE1 regulation in aging hepatocytes.