LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis
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 and IL-1β in macroph...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2015/125380 |
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| author | Yasuka Matsunaga Yusuke Nakatsu Toshiaki Fukushima Hirofumi Okubo Misaki Iwashita Hideyuki Sakoda Midori Fujishiro Takeshi Yamamotoya Akifumi Kushiyama Shin-ichiro Takahashi Yoshihiro Tsuchiya Hideaki Kamata Fuminori Tokunaga Kazuhiro Iwai Tomoichiro Asano |
| author_facet | Yasuka Matsunaga Yusuke Nakatsu Toshiaki Fukushima Hirofumi Okubo Misaki Iwashita Hideyuki Sakoda Midori Fujishiro Takeshi Yamamotoya Akifumi Kushiyama Shin-ichiro Takahashi Yoshihiro Tsuchiya Hideaki Kamata Fuminori Tokunaga Kazuhiro Iwai Tomoichiro Asano |
| author_sort | Yasuka Matsunaga |
| collection | DOAJ |
| description | 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 and IL-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. |
| format | Article |
| id | doaj-art-518430ed1f6b4770a0f90378e09b279f |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-518430ed1f6b4770a0f90378e09b279f2025-02-03T06:01:31ZengWileyMediators of Inflammation0962-93511466-18612015-01-01201510.1155/2015/125380125380LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic SteatohepatitisYasuka Matsunaga0Yusuke Nakatsu1Toshiaki Fukushima2Hirofumi Okubo3Misaki Iwashita4Hideyuki Sakoda5Midori Fujishiro6Takeshi Yamamotoya7Akifumi Kushiyama8Shin-ichiro Takahashi9Yoshihiro Tsuchiya10Hideaki Kamata11Fuminori Tokunaga12Kazuhiro Iwai13Tomoichiro Asano14Division 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, JapanDivision 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, JapanDivision 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, JapanDivision 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, JapanDivision of Cervico-Gnathostomatology, Department of Dental Science for Health Promotion, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Hiroshima Prefecture 734-8551, JapanDepartment of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDepartment of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDepartment of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanDivision of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, JapanDepartment of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, JapanDivision 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, JapanDivision 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, JapanLaboratory of Molecular Cell Biology Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, JapanDepartment of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, JapanDivision 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, JapanNonalcoholic 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 and IL-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.http://dx.doi.org/10.1155/2015/125380 |
| spellingShingle | Yasuka Matsunaga Yusuke Nakatsu Toshiaki Fukushima Hirofumi Okubo Misaki Iwashita Hideyuki Sakoda Midori Fujishiro Takeshi Yamamotoya Akifumi Kushiyama Shin-ichiro Takahashi Yoshihiro Tsuchiya Hideaki Kamata Fuminori Tokunaga Kazuhiro Iwai Tomoichiro Asano LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis Mediators of Inflammation |
| title | LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis |
| title_full | LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis |
| title_fullStr | LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis |
| title_full_unstemmed | LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis |
| title_short | LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis |
| title_sort | lubac formation is impaired in the livers of mice with mcd dependent nonalcoholic steatohepatitis |
| url | http://dx.doi.org/10.1155/2015/125380 |
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