title: LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis.
abstract: Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic lipid accumulation followed by the inflammation-induced death of hepatocytes and fibrosis. In this process, oxidative stress contributes to the induction of several inflammatory cytokines including TNF-α andIL-1β in macrophages, while, in hepatocytes, NF-κB reportedly induces the expressions of cell survival genes for protection from apoptosis. Recently, it was reported that the new ubiquitin ligase complex termed linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on NF-κB essential modulator (NEMO) and thereby induces NF-κB pathway activation. In this study, we demonstrated the formation of LUBAC to be impaired in the livers of NASH rodent models produced by methionine and choline deficient (MCD) diet feeding, first by either gel filtration or Blue Native-PAGE, with subsequent confirmation by western blotting. The reduction of LUBAC is likely to be attributable to markedly reduced expression of SHARPIN, one of its components. Thus, impaired LUBAC formation, which would result in insufficient NF-κB activation, may be one of the molecular mechanisms underlying the enhanced apoptotic response of hepatocytes in MCD diet-induced NASH livers.
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Yasuka
authors.initials: Y
authors.lastname: Matsunaga
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Okubo
authors.affiliation: Division of Cervico-Gnathostomatology, Department of Dental Science for Health Promotion, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Iwashita
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamotoya
authors.affiliation: Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.affiliation: Laboratory of Molecular Cell Biology Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Division of Molecular Medical Science, Department of Medical Chemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima Prefecture 734-8551, Japan.
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D002796:Choline Deficiency / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000032:analysis
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008715:Methionine; D010168:Palmitates; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C554944:Sipl1 protein, mouse; C492590:Rnf31 protein, mouse; C000607389:Rbck1 protein, mouse