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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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Autores principales: Yamaguchi, Takashi, Yoshida, Katsunori, Murata, Miki, Suwa, Kanehiko, Tsuneyama, Koichi, Matsuzaki, Koichi, Naganuma, Makoto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181097/
https://www.ncbi.nlm.nih.gov/pubmed/35682957
http://dx.doi.org/10.3390/ijms23116270
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author Yamaguchi, Takashi
Yoshida, Katsunori
Murata, Miki
Suwa, Kanehiko
Tsuneyama, Koichi
Matsuzaki, Koichi
Naganuma, Makoto
author_facet Yamaguchi, Takashi
Yoshida, Katsunori
Murata, Miki
Suwa, Kanehiko
Tsuneyama, Koichi
Matsuzaki, Koichi
Naganuma, Makoto
author_sort Yamaguchi, Takashi
collection PubMed
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.
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spelling pubmed-91810972022-06-10 Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis Yamaguchi, Takashi Yoshida, Katsunori Murata, Miki Suwa, Kanehiko Tsuneyama, Koichi Matsuzaki, Koichi Naganuma, Makoto Int J Mol Sci Review 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. MDPI 2022-06-03 /pmc/articles/PMC9181097/ /pubmed/35682957 http://dx.doi.org/10.3390/ijms23116270 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Yamaguchi, Takashi
Yoshida, Katsunori
Murata, Miki
Suwa, Kanehiko
Tsuneyama, Koichi
Matsuzaki, Koichi
Naganuma, Makoto
Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis
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 Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181097/
https://www.ncbi.nlm.nih.gov/pubmed/35682957
http://dx.doi.org/10.3390/ijms23116270
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