Administration of the potent PPAR? agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice

Ip, Emilia; Farrell, G; Hall, Pauline de la Μ.; Robertson, Graham; Leclercq, Isabelle

doi:10.1002/hep.20170

Cited by 344 publications

(308 citation statements)

References 49 publications

(70 reference statements)

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“…In the CCl 4 therapeutic model, the rank order of antifibrotic efficacy was IVA337 ≥ fenofibrate > rosiglitazone > GW501516, with PPARγ and PPARδ agonists having a partial effect on fibrosis. Our results are consistent with published studies on the effect of selective PPAR agonists on liver fibrosis 14, 21, 39. However, results with GW501516 in our study and in the literature differ from those obtained with KD3010, another PPARδ agonist that was shown to be very active on liver fibrosis induced by CCl 4 or bile duct ligation 39.…”

Section: Discussionsupporting

confidence: 91%

“…The selective PPARα agonist Wy14,643 improved steatosis, inflammation, and fibrosis in mice receiving a methionine‐ and choline‐deficient (MCD) diet and improved metabolic disorders, steatosis, and ballooning in high‐fat diet (HFD) fed foz/foz mice 14, 15. In patients, the PPARα agonist fenofibrate had limited efficacy on NASH but a significant effect on hepatocyte ballooning 16.…”

Section: Introductionmentioning

confidence: 99%

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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

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101

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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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Section: Discussionsupporting

confidence: 91%

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

Self Cite

101

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“…For example, Ip et al demonstrated that mice deficient in the expression of PPAR-α nuclear hormone receptor developed more severe steatohepatitis when fed MCDD compared to wild type mice (32). Conversely, treatment with the PPAR-α agonist Wy-14643 prevented and reversed hepatic pathologies induced by MCDD (33). Resolution of steatohepatitis by agonist was attributed to the induction of genes that facilitate fatty acid breakdown (e.g.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

Rivera

Adegboyega

Rooijen

et al. 2007

Journal of Hepatology

594

508

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BACKGROUND/AIMS-Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis.METHODS-Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intravenous injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGFβ, TNFα CD36 PPAR-α, liver fatty acid binding protein (L-FABP) and collagen α1.RESULTS-We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression.CONCLUSIONS-These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis.

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“…The resultant lowering of intrahepatic fat is sufficient to prevent or revert steatohepatitis. 9,15,16 Modulation of steatosis and inflammation by PPARgregulated adipocytokines was studied. 17,18 The link between PPAR-g and steatohepatitis was explored further by measuring the levels of adipocyte-derived cytokines (adipokines) such as adiponectin, TNF-a and IL-6.…”

Section: Role Of Pparc In Steatohepatitismentioning

confidence: 99%

PPARγ is essential for protection against nonalcoholic steatohepatitis

Chu

Lam

et al. 2010

Gene Ther

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Peroxisome proliferator-activated receptor-g (PPARg) is a transcription factor that regulates lipid metabolism and inflammatory responses. Certain PPARg ligands improve nonalcoholic steatohepatitis (NASH). The role of PPARg itself in NASH remains poorly understood. The functional consequences of PPARg in the development of steatohepatitis through gene deficiency or gene overexpression of PPARg delivered by adenovirus (Ad-PPARg) were examined. Our results show that PPARg-deficient (PPARg +/À ) mice fed the methionine-and choline-deficient (MCD) diet developed more severe steatohepatitis than wild-type mice, and were unaffected by PPARg ligand rosiglitazone. Overexpression of PPARg delivered by Ad-PPARg attenuated steatohepatitis. This effect was associated with redistribution of fatty acid from liver to adipose tissue by enhancing expression of fatty acid uptake genes (fatty acid binding protein-4 (aP2), fatty acid translocase (CD36), lipoprotein lipase (LPL) and fatty acid transport protein-1 (FATP-1)) and lipogenic genes (sterol regulatory element binding protein isoform-1 (SREBP-1) and stearoyl-CoA desaturase isoform-1 (SCD-1)) in adipose tissue and to a lesser extent in liver. The anti-steatohepatitis action of PPARg was also mediated via regulating adipokines through suppressing tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) and inducing adiponectin. Moreover, PPARg activation suppressed hepatic lipoperoxide and reduced hepatic pro-inflammatory cytokines (TNF-a and IL-6) production. In conclusion, PPARg is an important endogenous regulator and potential therapeutic target for nutritional steatohepatitis.

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Administration of the potent PPAR? agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice

Cited by 344 publications

References 49 publications

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

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

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

PPARγ is essential for protection against nonalcoholic steatohepatitis

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