Deletion of <i>Smad4</i> reduces hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression

Geng, Qin; Wang, Guo Zhen; Guo, Dan; Bai, Ru; Wang, Miao; Du, Sha

doi:10.1111/1751-2980.12599

Cited by 23 publications

(18 citation statements)

References 52 publications

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“…So far, Takahashi et al reported a decrease in liver mass and liver fat content after administration of TGF-β2 in high-fat diet (HFD) treated mice [231]. Also of relevance, knockout of Smad4 stimulated β-oxidation of fatty acids and suppressed lipid-induced fibrosis and inflammation in mouse livers [233]. The distinct metabolic roles of TGF-β1 and 2 again highlight the non-redundant functions of these TGF-β isoforms.…”

Section: Tgf-β and Metabolic Fate Changes In Liver Fibrosismentioning

confidence: 99%

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Dewidar

Meyer

Dooley

et al. 2019

Cells

519

363

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Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

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Section: Tgf-β and Metabolic Fate Changes In Liver Fibrosismentioning

confidence: 99%

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Dewidar

Meyer

Dooley

et al. 2019

Cells

519

363

View full text Add to dashboard Cite

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“…IPA analysis of the mouse models also identified pathways that were not predicted to be affected among human NASH datasets. Among these, the activation of SMAD2, SMAD4, YAP1, NOTCH1, EP300, p63, and the inhibition of nuclear receptor corepressor (NCOR) has been previously linked to human NASH by independent studies ( Table 3 ) [ 42 , 166 , 173 , 209 , 210 , 211 , 212 ]. Therefore, most mouse models mimic the transcriptional signature of human NASH for these transcription factors.…”

Section: Prediction Of Transcriptional Regulators By Database Analmentioning

confidence: 99%

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

2020

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Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.

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“…The findings of our literature survey confirmed the implication of the following: HSP90AB1 has been suggested as a possible biomarker in overweight and obese children with NAFLD [41]; HLA-B [42], CTNNB1 [43] and HSPA5 [44] are found to be abnormally expressed in NAFLD patients; CDKN1A polymorphism is associated with the development of human NAFLD [45]; TRAF1 has been also detected in NAFLD patients [46]; HSPB1 phosphorylation site has been differed between NAFLD cohorts [47]; SMAD4 was overexpresed in NASH patients [48]; SMAD2/3 phosphorylation and nuclear translocation documented in the liver of NASH patients[49]; RELA is well-known to cause inflammatory responses in NAFLD [50]; PIK3R3 has been proposed as an effective candidate target for the development of NAFLD [51]; GSK3B inhibition has been proposed as a possible therapeutic target to manipulate the NAFLD [52].…”

Section: Discussionmentioning

confidence: 99%

Construction and Analysis of Protein-Protein Interaction Network of Non-Alcoholic Fatty Liver Disease

Amanatidou

Dedoussis

2020

Preprint

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Non-alcoholic fatty liver disease (NAFLD) is a disease with multidimensional complexities. Many attempts have been made over the years to treat this disease but its incidence is rising. For this reason, the need to identify and study new candidate NAFLD biomarkers is of utmost importance. Systems-based approaches such as the analysis of protein-protein interaction (PPI) network could lead to the discovery of new disease biomarkers that can then be translated into clinical practice. The aim of this study is to analyze the interaction network of human proteins associated with NAFLD as well as their experimentally verified interactors and to propose new candidate proteins that may be involved in this disease. Computational analysis made it feasible to detect 77 candidate proteins associated with NAFLD, having high network scores. Furthemore, clustering analysis was performed to identify densely connected regions with biological significance in this network. Additionally, gene expression analysis was conducted to validate part of the findings of this research work. We believe that our research will be helpful in extending experimental efforts to address the pathogenesis and progression of NAFLD.

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Deletion of Smad4 reduces hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression

Abstract: Smad4 deletion may inhibit lipogenesis, stimulate β-oxidation, improve lipid metabolism and liver function, alleviate inflammation and fibrosis, and reduce cell apoptosis in NASH.

Cited by 23 publications

References 52 publications

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

Construction and Analysis of Protein-Protein Interaction Network of Non-Alcoholic Fatty Liver Disease

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