title: A Combination of Mitochondrial Oxidative Stress and Excess Fat/Calorie Intake Accelerates Steatohepatitis by Enhancing Hepatic CC Chemokine Production in Mice.
abstract: Mitochondrial oxidative stress is considered as a key accelerator of fibrosis in various organs including the liver. However, the production of oxidative stress and progression of liver fibrosis may merely represent the independent consequences of hepatocellular injury caused by the primary disease. Because of a lack of appropriate experimental models to evaluate the sole effects of oxidative stress, it is virtually unknown whether this stress is causatively linked to the progression of liver fibrosis. Here, we examined the direct effects of mitochondrial reactive oxygen species (ROS) on the progression of high fat/calorie diet-induced steatohepatitis using Tet-mev-1 mice, in which a mutated succinate dehydrogenase transgene impairs the mitochondrial electron transport and generates an excess amount of ROS in response to doxycycline administration. Wild type and Tet-mev-1 mice that had been continuously given doxycycline-containing water were subsequently fed either normal chow or a cholesterol-free high-fat/high-sucrose diet for 4 months at approximately 1 or 2 years of age. Histopathological examinations indicated that neither the mitochondrial ROS induced in Tet-mev-1 mice nor the feeding of wild type animals with high-fat/high-sucrose diet alone caused significant liver fibrosis. Only when the Tet-mev-1 mice were fed a high-fat/high-sucrose diet, it induced lipid peroxidation in hepatocytes and enhanced hepatic CC chemokine expression. These events were accompanied by increased infiltration of CCR5-positive cells and activation of myofibroblasts, resulting in extensive liver fibrosis. Interestingly, this combinatorial effect of mitochondrial ROS and excess fat/calorie intake on liver fibrosis was observed only in 2-year-old Tet-mev-1 mice, not in the 1-year-old animals. Collectively, these results indicate that mitochondrial ROS in combination with excess fat/calorie intake accelerates liver fibrosis by enhancing CC chemokine production in aged animals. We have provided a good experimental model to explore how high fat/calorie intake increases the susceptibility to nonalcoholic steatohepatitis in aged individuals who have impaired mitochondrial adaptation.
authors.affiliation: Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Kanagawa, Japan.|Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.|Research Laboratory, Minophagen Pharmaceutical Co. Ltd., Zama, Kanagawa, Japan.|CREST, Japan Science Technology/Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Moro
authors.affiliation: Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Kanagawa, Japan.|Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Kanagawa, Japan.|Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.|CREST, Japan Science Technology/Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Sumiyoshi
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.|Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazawa
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.|Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Support Center for Medical Research and Education, Research and Promotion Division (Isehara), Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Sato
authors.affiliation: Support Center for Medical Research and Education, Research and Promotion Division (Isehara), Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Iida
authors.affiliation: Support Center for Medical Research and Education, Research and Promotion Division (Isehara), Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Support Center for Medical Research and Education, Research and Promotion Division (Isehara), Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Support Center for Medical Research and Education, Research and Promotion Division (Isehara), Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.|CREST, Japan Science Technology/Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.|CREST, Japan Science Technology/Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Kanagawa, Japan.|Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.|Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.|CREST, Japan Science Technology/Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D059305:Diet, High-Fat / Q000009:adverse effects; D018450:Disease Progression; D002149:Energy Intake; D063990:Gene Ontology; D022781:Hepatocytes / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058977:Molecular Sequence Annotation; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: C000592874:CCR5 protein, mouse; D018925:Chemokines; D017382:Reactive Oxygen Species; D019713:Receptors, CCR5