Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype

Schnabl, Bernd; Purbeck, Carrie; Choi, You-kyung; Hagedorn, Curt H.; Brenner, David A.

doi:10.1053/jhep.2003.50097

Cited by 196 publications

(162 citation statements)

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“…In addition, expression of MMP-2 was upregulated by CM from steatotic hepatocytes. MMP- and has been previously characterized in detail [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we provide evidence that inhibition of cell cycle progression by the kinase inhibitor STS is sufficient to reliably induce apoptosis in activated human HSC. It is commonly believed that the observed protection from apoptosis in activated HSC is at least in part mediated via an increased expression of the anti-apoptotic proteins bcl-2 or bcl-xL [17,25]. In addition, direct interactions with ECM components leading to activation of the FAK/PI-3K-dependent survival pathway [26], and the secretion of TIMP-1 thereby preventing MMP-dependent matrix degradation [27] may promote the survival of activated HSC.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we used an immortalized activated human HSC line generated by ectopic expression of hTERT that has been characterized before [18,19].…”

Section: Cell Isolation and Cell Culturementioning

confidence: 99%

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Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

et al. 2009

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Abbreviations: CM (conditioned medium); FFAs (free fatty acids); HSC (hepatic stellate cells); NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); MMP (matrix-metallo-proteinase); NFκB (nuclear-factor κB); PHH (primary human hepatocytes); TIMP-1/-2 (tissue inhibitor of metallo-proteinase-1/-2) Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells (HSCs), the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media (CM) from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 (TIMP-1), TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.

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“…In addition, expression of MMP-2 was upregulated by CM from steatotic hepatocytes. MMP- and has been previously characterized in detail [18,19].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

et al. 2009

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“…In addition, activated NK cells also produce large amount of IFN-γ, which can induce HSC apoptosis and cell cycle arrest, as well as by enhancing NK cell killing of early activated HSC [131,132]. In addition, NK cells can selectively kill senescent activated HSC, which are cell cycle arrested cells that accumulate in fibrotic septa during chronic liver injury and become inefficient in ECM synthesis but able to up-regulate expression of extracellular matrixdegrading enzymes [133,134]. It has been proposed that senescence-activated HSCs express elevated levels of NK cell-activating ligands, becoming then sensitive to NK cell killing [133].…”

Section: Natural Killer and Natural Killer T Cells In Liver Fibrogenementioning

confidence: 99%

Cellular and molecular mechanisms in liver fibrogenesis

Novo

Cannito

Paternostro

et al. 2014

Archives of Biochemistry and Biophysics

178

194

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“…Molecular mechanisms governing HSC proliferation and extracellular matrix (ECM) synthesis differ in activated HSC depending on how far they are in the progression of the activated phenotype. Older, nonreplicating cells have increased expression of inflammatory genes and decreased expression of ECM genes compared with younger, replicating HSC (35).…”

mentioning

confidence: 99%

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α₅β₁-integrin

Dodig¹,

Ogunwale²,

Dasarathy³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hepatic stellate cells (HSC) differ in their phenotype depending on the initiation and progression of their activation. Our hypothesis was that different mechanisms govern type I collagen synthesis depending on stage of HSC activation. We investigated the role of ␣5␤1-integrin as a regulator of type I collagen gene COL1A1 expression in primary and passaged HSC cultures using transgenic mouse containing type I collagen gene COL1A1 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene. The ␣5␤1 protein levels increased during the activation and were highest in day 6 primary cultures but decreased in passaged HSC. CAT activity, reflecting COL1A1 expression, was upregulated by ␣5␤1-integrin. Inhibition of ␣5␤1-integrin by echistatin and blocking antibody resulted in reduced transgene activity only in early primary cultures (compared with the control, 53.3 Ϯ 12% echistatin and 58.8 Ϯ 7% blocking antibody, respectively, P Ͻ 0.05). Treatment of passaged HSC with either echistatin or blocking antibody had no effect. Fibronectin, an ␣5␤1-integrin ligand, increased transgene activity in primary (210 Ϯ 33%, P Ͻ 0.05) but not in passaged HSC cultures (119 Ϯ 8%). This ␣5␤1-integrin effect appears to be at least in part mediated by CCAAT enhancer binding protein-␤ (C/EBP␤), because fibronectin increased and ␣5-gene silencing by small interfering RNA decreased C/EBP␤ levels. In addition, C/EBP␤ knockout mice showed reduced type I collagen synthesis compared with wild-type littermates. Therefore ␣5␤1-integrin is an important regulator of type I collagen production in early primary HSC cultures but appears to have no direct role once the HSC are fully activated.

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Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype

Cited by 196 publications

References 50 publications

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

Cellular and molecular mechanisms in liver fibrogenesis

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α₅β₁-integrin

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Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype

Cited by 196 publications

References 50 publications

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

Cellular and molecular mechanisms in liver fibrogenesis

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α5β1-integrin

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Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α₅β₁-integrin