Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells

Marra, Fabio; Efsen, Eva; Romanelli, Roberto Giulio; Caligiuri, Alessandra; Pastacaldi, Sabrina; Batignani, Giacomo; Bonacchi, Andrea; Caporale, Roberto; Laffi, Giacomo; Pinzani, Massimo; Geñtilini, Paolo

doi:10.1053/gast.2000.9365

Cited by 393 publications

(312 citation statements)

References 49 publications

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“…PPARγ ligands exhibited a marked growth inhibitory potential on hepatocellular carcinoma cells through induction of G1 cell cycle arrest and recent studies have also shown that activation of PPARγ can inhibit the profibrogenic and proinflammatory actions of hepatic stellate cells (Galli et al, 2000;Marra et al, 2000;Miyahara et al, 2000). Taken together, we conclude that PPARγ ligands may also prove beneficial for primary or secondary chemoprevention of hepatocellular carcinoma.…”

Section: Discussionsupporting

confidence: 62%

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

et al. 2001

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Summary Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been implicated in the growth inhibition and differentiation of certain human cancers with diverse tissue origin. In this study, expression of PPARγ in human hepatocellular carcinoma (HCC) and the effect of PPARγ ligands on HCC cells were investigated in vitro using Hep G2, HuH-7, KYN-1 and KYN-2 cell lines. All cell lines were found to express functionally active PPARγ and a marked growth inhibition was induced by thiazolidinedione ligands troglitazone, and pioglitazone as well as with its natural ligand 15-deoxy-∆ 12,14 -prostaglandin J 2 . The growth inhibitory effect was associated with a dose-dependent inhibition of DNA synthesis, cell cycle progression and α fetoprotein expression.

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Section: Discussionsupporting

confidence: 62%

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

et al. 2001

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“…Although the level of PPAR-␥ is dramatically reduced in activated HSCs, it still responds to its agonists, leading to inhibition of HSC activation and suppression of collagen gene expression in vitro and in vivo (23,34,37). We (55) have shown that curcumin induces gene expression of PPAR-␥ and stimulates its trans-activation activity in activated HSCs in vitro.…”

Section: Activation Of Ppar-␥ Results In Inhibition Of Ctgf Gene Exprmentioning

confidence: 99%

“…During hepatic fibrogenesis, quiescent HSCs become active, a process that is characterized by increased cell proliferation and excessive production and deposition of connective tissue elements and ECM, including ␣I(I)-collagen. The activation of HSCs is coupled to a dramatic reduction in the level of peroxisome proliferator-activated receptor (PPAR)-␥ (23,34,37). Prior studies have implicated a potential therapeutic value of PPAR-␥ activation in the treatment of liver fibrosis (23,34,37).…”

mentioning

confidence: 99%

“…The activation of HSCs is coupled to a dramatic reduction in the level of peroxisome proliferator-activated receptor (PPAR)-␥ (23,34,37). Prior studies have implicated a potential therapeutic value of PPAR-␥ activation in the treatment of liver fibrosis (23,34,37). Curcumin, the active ingredient of the rhizome of the plant turmeric (Curcuma longa Linn), possesses antiproliferative, antioxidant, anti-inflammatory, antiangiogenic, and antitumor effects (16,38,39,46).…”

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confidence: 99%

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Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor

Zheng

Chen²

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The PPARδ isoform (also known as PPARβ) contributes to the regulation of glucose and lipid metabolism while exerting anti‐inflammatory properties in the liver by skewing M2 polarization of Küpffer cells 9, 10, 11. PPARγ and PPARδ are expressed at various levels in hepatic stellate cells (HSCs), a driver of liver fibrosis; PPARγ is key in keeping HSCs in a quiescent nonfibrogenic state 12, 13…”

Section: Introductionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

114

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IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

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Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells

Cited by 393 publications

References 49 publications

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

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