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

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease worldwide and is estimated to affect nearly a third of the population. Huwe1, also known as ARF-BP1, MULE, and HectH9, is a HECT (homology to E6-APC terminus)-domain E3 ubiquitin ligase originally identified as a binding partner of the tumor suppressor ARF, as well as a direct negative regulator of the tumor suppressor p53. To further elucidate the in vivo role of Huwe1, we generated a liver-specific Huwe1 (Huwe1LKO) knockout mouse model. Surprisingly, liver-specific knockout of Huwe1 protected mice from the development of age-induced hepatic steatosis. To elucidate the mechanism underlying this phenotype, bulk RNAseq analysis was performed on liver tissues from 1-year-old Huwe1LKO and Huwe1WTmice. Bulk RNAseq was performed on livers from 1-year-old Huwe1 knockout mice as compared to wildtype mice. 4 livers were sequenced per group.