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Int. J. Mol. Sci. 2017, 18(2), 326;

Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
CellBiology Unit, Institute of Innovative Research, Tokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, Japan
Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, Chuo-ku, Tokyo 103-0002, Japan
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan
Laboratory of Pathobiochemistry, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585, Japan
Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Authors to whom correspondence should be addressed.
Academic Editors: Rolf Teschke and Gaby Danan
Received: 9 January 2017 / Revised: 26 January 2017 / Accepted: 26 January 2017 / Published: 4 February 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
Full-Text   |   PDF [6585 KB, uploaded 4 February 2017]   |  


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 nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity. View Full-Text
Keywords: LUBAC; CCl4 and APAP-induced hepatitis; inflammation; fibrosis; hepatocyte apoptosis LUBAC; CCl4 and APAP-induced hepatitis; inflammation; fibrosis; hepatocyte apoptosis

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Yamamotoya, T.; Nakatsu, Y.; Matsunaga, Y.; Fukushima, T.; Yamazaki, H.; Kaneko, S.; Fujishiro, M.; Kikuchi, T.; Kushiyama, A.; Tokunaga, F.; Asano, T.; Sakoda, H. Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice. Int. J. Mol. Sci. 2017, 18, 326.

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