Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAF...
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| author | Takashi Yamaguchi Katsunori Yoshida Miki Murata Kanehiko Suwa Koichi Tsuneyama Koichi Matsuzaki Makoto Naganuma |
| author_facet | Takashi Yamaguchi Katsunori Yoshida Miki Murata Kanehiko Suwa Koichi Tsuneyama Koichi Matsuzaki Makoto Naganuma |
| author_sort | Takashi Yamaguchi |
| collection | DOAJ |
| description | Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis. |
| first_indexed | 2024-03-10T01:14:28Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:14:28Z |
| publishDate | 2022-06-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b58e456255e84bc78622890c2c2bc11c2023-11-23T14:12:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012311627010.3390/ijms23116270Smad3 Phospho-Isoform Signaling in Nonalcoholic SteatohepatitisTakashi Yamaguchi0Katsunori Yoshida1Miki Murata2Kanehiko Suwa3Koichi Tsuneyama4Koichi Matsuzaki5Makoto Naganuma6Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, JapanDepartment of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, JapanDepartment of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, JapanDepartment of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, JapanDepartment of Pathology & Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, JapanDepartment of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, JapanNonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis.https://www.mdpi.com/1422-0067/23/11/6270nonalcoholic steatohepatitisSmadtransforming growth factor-βhepatocellular carcinoma |
| spellingShingle | Takashi Yamaguchi Katsunori Yoshida Miki Murata Kanehiko Suwa Koichi Tsuneyama Koichi Matsuzaki Makoto Naganuma Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis International Journal of Molecular Sciences nonalcoholic steatohepatitis Smad transforming growth factor-β hepatocellular carcinoma |
| title | Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis |
| title_full | Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis |
| title_fullStr | Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis |
| title_full_unstemmed | Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis |
| title_short | Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis |
| title_sort | smad3 phospho isoform signaling in nonalcoholic steatohepatitis |
| topic | nonalcoholic steatohepatitis Smad transforming growth factor-β hepatocellular carcinoma |
| url | https://www.mdpi.com/1422-0067/23/11/6270 |
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