PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression1

Sun, Kai; Wang, Qian; Huang, Xiaohui

doi:10.1111/j.1745-7254.2006.00299.x

Cited by 66 publications

(62 citation statements)

References 34 publications

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“…According to these authors, GW7845 may prevent adipocytic HSCs by acquiring a myofibroblastic phenotype during chronic liver injury [183]. These results were confirmed in another in vitro study on HSCs rat in which GW7845 inhibited the growth of HSCs and TGF 1-induced CTGF expression, thus confirming itself as a potential antifibrotic compound in treating and preventing liver fibrosis [247].…”

Section: Ppar Agonistssupporting

confidence: 72%

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

Zardi¹,

Navarini²,

Sambataro³

et al. 2013

CMC

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Abstr act: Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

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Section: Ppar Agonistssupporting

confidence: 72%

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

Zardi¹,

Navarini²,

Sambataro³

et al. 2013

CMC

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“…PPARγ ligands also inhibit expression of TGFβ1-regulated genes, such as connective tissue growth factor (CTGF) in activated, myofibroblastic HSC (19). However, the mechanisms involved may differ.…”

Section: Discussionmentioning

confidence: 99%

PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells

Zhao

Chen

Yang

et al. 2006

Biochemical and Biophysical Research Communications

130

107

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PPARγ agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPARγ agonists inhibit transforming growth factor (TGF)β1-activation of TGFβ receptor (TGFβR)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1αI. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPARγ expression and transcriptional activity. These adipocytic HSC were then treated with TGFβ1 ± a TGFβR-1 kinase inhibitor (SB431542) or a PPARγ agonist (GW7845). TGFβ1 caused dose-and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGFβR-1 kinase inhibitor, the PPARγ agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPARγ agonists reflect their ability to inhibit TGFβ1-TGFβR1 signaling that initiates ECM gene expression in quiescent HSC.

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“…Expression of CTGF in HSCs is up-regulated by numerous profibrotic factors, including TGF-␤ (4,18,19), endothelin-1 (20), PDGF-BB, acetaldehyde (21), ethanol (22), and the Th2 cytokine IL-13 (23,24), with TGF-␤ being the most important trigger as elevated TGF-␤ levels are observed in almost all fibrotic liver diseases, irrespective of etiology. Although in vitro experiments have shown that TGF-␤ plays only a minor role in CTGF production in quiescent HSCs (20,23,24), activated HSCs as well as established HSC cell lines secrete high levels of CTGF in response to TGF-␤ treatment (22,23).…”

Section: Connective Tissue Growth Factor (Ctgf)mentioning

confidence: 99%