Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis
Abstract
:1. Introduction
2. Differential Patterns of Carcinogenesis in NASH: A Carcinogenic Sequence from Chronic Inflammation via Progressive Fibrosis versus Carcinogenesis Requiring No Inflammation or Progressive Fibrosis
3. Chronic Inflammation Is Triggered via a Complex Pathway Leading from Steatosis to NASH to Fibrogenesis
3.1. Directly or Indirectly, Oxidative Stress Stimulates Liver Fibrosis through Increases in Pro-Inflammatory Cytokines and Lipotoxicity
3.2. Cytokines Derived from Adipose Tissue Mediate Chronic Inflammation Leading to Insulin Resistance in NASH
3.3. Inflammation in the Absence of Pathogens Leads to Liver Injury and Fibrogenesis in NASH
3.4. During Chronic Inflammation-Mediated NASH Pathogenesis, TGF-β Signaling Prompts Conversion of HSC to MFB
3.5. Chronic Inflammation Shifts Hepatocytic Smad3 Phospho-Isoform Signaling from Tumor Suppression to Carcinogenesis, Increasing Risk of HCC
4. Inflammation-Independent Process of Hepatocarcinogenesis
4.1. Oxidative Stress Associated with Insulin Resistance and Lipotoxicity Can Mediate Carcinogenesis Even without Inflammation or Fibrogenesis
4.2. The Mutational Landscape of NASH-HCC
4.3. Even without Chronic Inflammation and Progressive Fibrosis, Inflammation-Independent Hepatic Carcinogenesis May Arise from Genetic or Epigenetic Alterations
5. Analysis of Phospho-Smad Signaling Is Useful for Targeting High-Risk NASH Patients Who Require Intense Surveillance for HCC
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Triggers | Mechanisms | Effect | Reference |
---|---|---|---|
Oxidative stress | Pro-inflammatory cytokines | Inflammation | [54] |
TNFR1 expression | |||
Lipid peroxidation | |||
HSC activation | Fibrosis | [126,127,128,129] | |
Oncogenic mutation | DNA damage | ||
Lipotoxicity | Pro-inflammatory cytokines | Inflammation | [55] |
ER stress | DNA damage | [63,64,65] | |
Adipose tissue | Adiponectin | Inflammation | [57,58] |
Insulin resistance | |||
PAMPs | KC and HSC activation | Inflammation | [69,70,72] |
Fibrosis |
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Yamaguchi, T.; Yoshida, K.; Murata, M.; Suwa, K.; Tsuneyama, K.; Matsuzaki, K.; Naganuma, M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. Int. J. Mol. Sci. 2022, 23, 6270. https://doi.org/10.3390/ijms23116270
Yamaguchi T, Yoshida K, Murata M, Suwa K, Tsuneyama K, Matsuzaki K, Naganuma M. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. International Journal of Molecular Sciences. 2022; 23(11):6270. https://doi.org/10.3390/ijms23116270
Chicago/Turabian StyleYamaguchi, Takashi, Katsunori Yoshida, Miki Murata, Kanehiko Suwa, Koichi Tsuneyama, Koichi Matsuzaki, and Makoto Naganuma. 2022. "Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis" International Journal of Molecular Sciences 23, no. 11: 6270. https://doi.org/10.3390/ijms23116270
APA StyleYamaguchi, T., Yoshida, K., Murata, M., Suwa, K., Tsuneyama, K., Matsuzaki, K., & Naganuma, M. (2022). Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. International Journal of Molecular Sciences, 23(11), 6270. https://doi.org/10.3390/ijms23116270