TGF-β and hepatocyte transdifferentiation in liver fibrogenesis

S, Dooley; Hamzavi, J; Ciuclan, L; Godoy, P; Ilkavets, I; Ehnert, S; Ueberham, E; Gebhardt, R; Kanzler, S; Geier, A; Breitkopf, K; Weng, HL; Mertens, PR

doi:10.1055/s-2008-1037471

Cited by 7 publications

(13 citation statements)

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“…Recent progress in alcohol research has revealed novel mechanisms, such as the discovery of sphingomyelinases playing a role in the TNF-a induced heptaocyte cell death and fibrogenesis (Marı´and Ferna´ndez-Checa, 2007;Marıé t al., 2004); TFG-b-mediated regulation of Cyp21A1 and ADH1 contributing toward liver fat accumulation and oxidative stress, and the antagonistic action of Smad 7 at different stages and locations of TGF-b-mediated signaling in ALD (Dooley et al, 2001(Dooley et al, , 2008. Regulation of plasmin homeostasis through PAI-1 (Arteel, 2008;Seth et al, 2008) and other fibrinolysis regulating molecules, such as osteopontin (Opn) (Apte et al, 2005b;Seth et al, 2006a,b) are also some of the recent discoveries that provide insights in the common mechanisms involved in alcohol-induced organ injury.…”

Section: Novel Mechanisms Of Alcohol Injury In Diverse Organs and Tismentioning

confidence: 99%

“…Emerging evidence implicates hepatocytes as a source of pro-fibrogenic fibroblastoid cells by virtue of undergoing epithelial to mesenchymal transition (EMT) in chronic liver injury (Dooley et al, 2008;Kaimori et al, 2007;Zeisberg et al, 2007). This change is driven by active TGF-b signaling.…”

Section: Role Of Hepatocytes: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

“…The TGF-b-mediated switch of phenotype is not only valid in hepatocellular carcinoma cells, but also in adult, nontransformed hepatocytes. A recent study demonstrated that TGF-b-induced apoptosis occurred only in a minor fraction of cultured hepatocytes (Dooley et al, 2008). The majority of hepatocytes lost epithelial characteristics and acquired a mesenchymal phenotype, called EMT, regulated by a switch in the cell's expression pattern.…”

Section: Role Of Hepatocytes: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

“…Among others, Smad target genes include ECM-related molecules such as (plasminogen activator inhibitor-1) PAI-1, urokinase plasminogen activator (uPA), and collagen. TGF-b signaling activates several positive and negative feedback mechanisms, particularly through Smad7, a key negative feedback participant that modulates TGF-b signaling in a site-and stagespecific manner (Dooley et al, 2008;Nakao et al, 1997;Shi and Massague, 2003;Shi et al, 2004;Zhang et al, 2007). In hepatocytes, these feedback mechanisms tightly regulate TGF-b signaling in order to check excessive apoptosis and inhibition of proliferation.…”

Section: Tgf-b-mediated Signalingmentioning

confidence: 99%

“…Several cell types are involved in this process, predominantly stellate cells and macrophages. Recent studies demonstrate that parenchymal cells, such as hepatocytes also play a major role in alcohol-induced pathogenesis (Dooley et al, 2008;Zeisberg et al, 2007). Advances in delineating the molecular mechanisms in alcohol-mediated tissue injury have been made mostly with alcoholic liver disease (ALD) which has also served as a model for alcohol damage in other organs.…”

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confidence: 99%

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Alcohol, Signaling, and ECM Turnover

Seth

El-Guindy

Apte

et al. 2009

Alcoholism Clin & Exp Res

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Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.

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Section: Novel Mechanisms Of Alcohol Injury In Diverse Organs and Tismentioning

confidence: 99%

Section: Role Of Hepatocytes: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

Section: Role Of Hepatocytes: Epithelial To Mesenchymal Transitionmentioning

confidence: 99%

Section: Tgf-b-mediated Signalingmentioning

confidence: 99%

mentioning

confidence: 99%

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Alcohol, Signaling, and ECM Turnover

Seth

El-Guindy

Apte

et al. 2009

Alcoholism Clin & Exp Res

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Aloin Attenuates Oxidative Stress, Inflammation, and CCl₄-Induced Liver Fibrosis in Mice: Possible Role of TGF-β/Smad Signaling

Bai,

Qian,

Cai

et al. 2023

J. Agric. Food Chem.

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Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure

Humeres¹,

Shinde²,

Hanna³

et al. 2022

Journal of Clinical Investigation

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Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts. However, TGF-β–driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7, may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of nonreperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA + infarct myofibroblasts, but not in α-SMA – PDGFRα + fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure–related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 effects on TGF-β cascades involved deactivation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with ErbB2 in a TGF-β–independent manner and restrained ErbB1/ErbB2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins, and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β–induced negative feedback mechanism that inhibits postinfarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-β–independent fibrogenic actions of ErbB2.

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TGF-β and hepatocyte transdifferentiation in liver fibrogenesis

Cited by 7 publications

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Alcohol, Signaling, and ECM Turnover

Alcohol, Signaling, and ECM Turnover

Aloin Attenuates Oxidative Stress, Inflammation, and CCl₄-Induced Liver Fibrosis in Mice: Possible Role of TGF-β/Smad Signaling

Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure

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TGF-β and hepatocyte transdifferentiation in liver fibrogenesis

Cited by 7 publications

References 0 publications

Alcohol, Signaling, and ECM Turnover

Alcohol, Signaling, and ECM Turnover

Aloin Attenuates Oxidative Stress, Inflammation, and CCl4-Induced Liver Fibrosis in Mice: Possible Role of TGF-β/Smad Signaling

Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure

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Product

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Aloin Attenuates Oxidative Stress, Inflammation, and CCl₄-Induced Liver Fibrosis in Mice: Possible Role of TGF-β/Smad Signaling