Hepatic Huwe1 loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring.

Non-alcoholic fatty liver disease (NAFLD) is the most pervasive liver pathology worldwide. Here, we demonstrate that the ubiquitin E3 ligase Huwe1 is vital in NAFLD pathogenesis. Using mass spectrometry and RNA sequencing, we reveal that liver-specific deletion of Huwe1 (Huwe1LKO) in 1-year-old mice (approximately middle age in humans) elicits extensive lipid metabolic reprogramming that involves downregulation of de novo lipogenesis and fatty acid uptake, upregulation of fatty acid β-oxidation, and increased oxidative phosphorylation. ChEA transcription factor prediction analysis inferred these changes result from attenuated PPARɑ, LXR, and RXR activity in Huwe1LKO livers. Consequently, Huwe1LKO mice fed chow diet exhibited significantly reduced hepatic steatosis and superior glucose tolerance compared to wild-type mice. Huwe1LKO also conferred protection from high-fat diet-induced hepatic steatosis by 6-months of age, with increasingly robust differences observed as mice reached middle age. Together, we present evidence that Huwe1 plays a critical role in the development of age- and diet-induced NAFLD.