Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis
Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, S...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-06-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI151895 |
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| author | Satoshi Kawamura Yuki Matsushita Shigeyuki Kurosaki Mizuki Tange Naoto Fujiwara Yuki Hayata Yoku Hayakawa Nobumi Suzuki Masahiro Hata Mayo Tsuboi Takahiro Kishikawa Hiroto Kinoshita Takuma Nakatsuka Masaya Sato Yotaro Kudo Yujin Hoshida Atsushi Umemura Akiko Eguchi Tsuneo Ikenoue Yoshihiro Hirata Motonari Uesugi Ryosuke Tateishi Keisuke Tateishi Mitsuhiro Fujishiro Kazuhiko Koike Hayato Nakagawa |
| author_facet | Satoshi Kawamura Yuki Matsushita Shigeyuki Kurosaki Mizuki Tange Naoto Fujiwara Yuki Hayata Yoku Hayakawa Nobumi Suzuki Masahiro Hata Mayo Tsuboi Takahiro Kishikawa Hiroto Kinoshita Takuma Nakatsuka Masaya Sato Yotaro Kudo Yujin Hoshida Atsushi Umemura Akiko Eguchi Tsuneo Ikenoue Yoshihiro Hirata Motonari Uesugi Ryosuke Tateishi Keisuke Tateishi Mitsuhiro Fujishiro Kazuhiko Koike Hayato Nakagawa |
| author_sort | Satoshi Kawamura |
| collection | DOAJ |
| description | Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment. |
| first_indexed | 2024-12-12T12:11:14Z |
| format | Article |
| id | doaj.art-ed503c19945242ac8be07a0dfec98388 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T12:11:14Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-ed503c19945242ac8be07a0dfec983882022-12-22T00:24:52ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-06-0113211Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitisSatoshi KawamuraYuki MatsushitaShigeyuki KurosakiMizuki TangeNaoto FujiwaraYuki HayataYoku HayakawaNobumi SuzukiMasahiro HataMayo TsuboiTakahiro KishikawaHiroto KinoshitaTakuma NakatsukaMasaya SatoYotaro KudoYujin HoshidaAtsushi UmemuraAkiko EguchiTsuneo IkenoueYoshihiro HirataMotonari UesugiRyosuke TateishiKeisuke TateishiMitsuhiro FujishiroKazuhiko KoikeHayato NakagawaEnhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.https://doi.org/10.1172/JCI151895Gastroenterology |
| spellingShingle | Satoshi Kawamura Yuki Matsushita Shigeyuki Kurosaki Mizuki Tange Naoto Fujiwara Yuki Hayata Yoku Hayakawa Nobumi Suzuki Masahiro Hata Mayo Tsuboi Takahiro Kishikawa Hiroto Kinoshita Takuma Nakatsuka Masaya Sato Yotaro Kudo Yujin Hoshida Atsushi Umemura Akiko Eguchi Tsuneo Ikenoue Yoshihiro Hirata Motonari Uesugi Ryosuke Tateishi Keisuke Tateishi Mitsuhiro Fujishiro Kazuhiko Koike Hayato Nakagawa Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis The Journal of Clinical Investigation Gastroenterology |
| title | Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis |
| title_full | Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis |
| title_fullStr | Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis |
| title_full_unstemmed | Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis |
| title_short | Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis |
| title_sort | inhibiting scap srebp exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis |
| topic | Gastroenterology |
| url | https://doi.org/10.1172/JCI151895 |
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