Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis
Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully un...
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2022-05-01
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| author | Yosuke Inomata Jae-Won Oh Kohei Taniguchi Nobuhiko Sugito Nao Kawaguchi Fumitoshi Hirokawa Sang-Woong Lee Yukihiro Akao Shinji Takai Kwang-Pyo Kim Kazuhisa Uchiyama |
| author_facet | Yosuke Inomata Jae-Won Oh Kohei Taniguchi Nobuhiko Sugito Nao Kawaguchi Fumitoshi Hirokawa Sang-Woong Lee Yukihiro Akao Shinji Takai Kwang-Pyo Kim Kazuhisa Uchiyama |
| author_sort | Yosuke Inomata |
| collection | DOAJ |
| description | Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression. |
| first_indexed | 2024-03-10T04:03:55Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:03:55Z |
| publishDate | 2022-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fea4ebd1d564445a912926f24599687a2023-11-23T08:29:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-01239523010.3390/ijms23095230Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic SteatohepatitisYosuke Inomata0Jae-Won Oh1Kohei Taniguchi2Nobuhiko Sugito3Nao Kawaguchi4Fumitoshi Hirokawa5Sang-Woong Lee6Yukihiro Akao7Shinji Takai8Kwang-Pyo Kim9Kazuhisa Uchiyama10Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanDepartment of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, KoreaTranslational Research Program, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, JapanDepartment of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanDepartment of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanDepartment of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, JapanDepartment of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanDepartment of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, KoreaDepartment of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, JapanNon-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.https://www.mdpi.com/1422-0067/23/9/5230NASHmicroRNA (miRNA)miR-122-5pPKM2Kupffer cellsmacrophages |
| spellingShingle | Yosuke Inomata Jae-Won Oh Kohei Taniguchi Nobuhiko Sugito Nao Kawaguchi Fumitoshi Hirokawa Sang-Woong Lee Yukihiro Akao Shinji Takai Kwang-Pyo Kim Kazuhisa Uchiyama Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis International Journal of Molecular Sciences NASH microRNA (miRNA) miR-122-5p PKM2 Kupffer cells macrophages |
| title | Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis |
| title_full | Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis |
| title_fullStr | Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis |
| title_full_unstemmed | Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis |
| title_short | Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis |
| title_sort | downregulation of mir 122 5p activates glycolysis via pkm2 in kupffer cells of rat and mouse models of non alcoholic steatohepatitis |
| topic | NASH microRNA (miRNA) miR-122-5p PKM2 Kupffer cells macrophages |
| url | https://www.mdpi.com/1422-0067/23/9/5230 |
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