title: Activation of the Nrf2-ARE pathway in hepatocytes protects against steatosis in nutritionally induced non-alcoholic steatohepatitis in mice.
abstract: Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2- animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2- and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model.
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
authors.forename: Lung-Yi
authors.initials: LY
authors.lastname: Lee
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
authors.forename: Ulrike A
authors.initials: UA
authors.lastname: Köhler
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
authors.forename: Drew
authors.initials: D
authors.lastname: Roenneburg
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waism
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin *Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland, Divisions of Pharmaceutical Sciences, Molecular and Environmental Toxicology Center, Center for Neuroscience, Waisman Center, University of Wisconsin, Madison, Wisconsin 53705 and Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin foley@surgery.wisc.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Foley
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D015153:Blotting, Western; D004032:Diet; D015870:Gene Expression / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000235:genetics; D008111:Liver Function Tests; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014280:Triglycerides
keywords: NASH; Nrf2; antioxidants; liver; steatosis; transgenic mice