Next Article in Journal
The Fungal Mycobiome and Its Interaction with Gut Bacteria in the Host
Next Article in Special Issue
A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats
Previous Article in Journal
Sphingosine Kinase-1 Involves the Inhibitory Action of HIF-1α by Chlorogenic Acid in Hypoxic DU145 Cells
Article Menu
Issue 2 (February) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2017, 18(2), 326; doi:10.3390/ijms18020326

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

1
Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
2
CellBiology Unit, Institute of Innovative Research, Tokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, Japan
3
Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, Chuo-ku, Tokyo 103-0002, Japan
4
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
5
Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan
6
Laboratory of Pathobiochemistry, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585, Japan
7
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)
View Full-Text   |   Download PDF [6585 KB, uploaded 4 February 2017]   |  

Abstract

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
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top