Hepatic Huwe1 loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring
William W. Feng,
Scott Bang,
Eric M. Takacs,
Cora Day,
Katherine J. Crawford,
Ruba Al-Sheyab,
Dara B. Almufarrej,
Wendy Wells,
Serguei Ilchenko,
Takhar Kasumov,
Ning Kon,
Colleen M. Novak,
Wei Gu,
Manabu Kurokawa
Affiliations
William W. Feng
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Scott Bang
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Eric M. Takacs
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Cora Day
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Katherine J. Crawford
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Ruba Al-Sheyab
School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA
Dara B. Almufarrej
School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA
Wendy Wells
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
Serguei Ilchenko
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
Takhar Kasumov
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
Ning Kon
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Colleen M. Novak
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA; School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA
Wei Gu
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Manabu Kurokawa
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA; School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA; Corresponding author
Summary: 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.
