Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARδ agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet

Nagasawa, Tatsuya; Inada, Yoichi; Nakano, Shigeru; Tamura, Toru; Takahashi, Tetsuaki; Maruyama, Kazuyasu; Yamazaki, Yoshinobu; Kuroda, Junji; Shibata, Nobuhiko

doi:10.1016/j.ejphar.2006.02.028

Cited by 221 publications

(188 citation statements)

References 35 publications

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“…64 Similarly, administration of GW501516 is protective against liver toxicity induced by choline deficiency, which may be due to antiinflammatory effects including inhibition of NF-B-dependent signaling and stellate cell activation. 65 Combined, these latter 2 observations are consistent with the hypothesis that ligand activation of PPAR␤/␦ could protect against liver toxicity induced by AOM and CCl 4 , as suggested from the current studies. However, it also remains possible that the effects observed in the PPAR␤/ ␦-null mouse are attributable to ligand-independent modulation of intracellular processes.…”

Section: Discussionsupporting

confidence: 79%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2007

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Potential functional roles for the peroxisome proliferator-activated receptor-␤/␦ (PPAR␤/␦) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPAR␤/␦ is expressed in liver, its function in this tissue is less clear. To determine the role of PPAR␤/␦ in chemically induced liver toxicity, wild-type and PPAR␤/␦-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPAR␤/␦-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl 4 ) hepatoxicity was also observed in PPAR␤/␦-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl 4 were observed between wild-type or PPAR␤/␦-null mice in response to CCl 4 . Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-B) activity were noted in PPAR␤/␦-null mice. Conclusion:Results from these studies show that PPAR␤/␦ is protective against liver toxicity induced by AOM and CCl 4 , suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (HEPATOLOGY 2008;47:225-235.)

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Section: Discussionsupporting

confidence: 79%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2007

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“…Therefore, the absence of PPARa upregulation in lipid-loaded FaO cells may depend on the excess oleate versus palmitate (2:1) in the FFA mixture, and this excess oleate may also explain the decrease in the transcription of SCD1 observed in lipid-loaded FaO cells, since this enzyme synthesizes oleic acid. On the other hand, the downregulation of PPARd observed in lipid-loaded FaO cells fits well with previous reports showing an opposite regulation of PPARd and PPARg in ob/ob mice (Roberts et al 2009 Indeed, PPARd was shown to increase the synthesis of high-density lipoproteins, to inhibit LD formation in the liver, and to enhance FFA catabolism and energy uncoupling in adipose tissue and muscle (Wang et al 2003, Nagasawa et al 2006. Therefore, the concomitant downregulation of PPARd and upregulation of PPARg in lipid-loaded FaO cells may sustain inhibition of FFA oxidation and secretion, and promote their storage into LDs.…”

Section: Discussionsupporting

confidence: 76%

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

Grasselli

Voci

Canesi

et al. 2011

Journal of Endocrinology

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Iodothyronines influence lipid metabolism and energy homeostasis. Previous studies demonstrated that 3,5-L-diiodothyronine (T 2 ), as well as 3,3 0 ,5-L-triiodothyronine (T 3 ), was able to both prevent and reverse hepatic steatosis in rats fed a high-fat diet, and this effect depends on a direct action of iodothyronines on the hepatocyte. However, the involvement of thyroid hormone receptors (TRs) in mediating the lipid-lowering effect of iodothyronines was not elucidated. In this study, we investigated the ability of T 2 and T 3 to reduce the lipid overloading using the rat hepatoma FaO cells defective for functional TRs. The absence of constitutive mRNA expression of both TRa1 and TRb1 in FaO cells was verified by RT-qPCR. To mimic the fatty liver condition, FaO cells were treated with a fatty acid mixture and then exposed to pharmacological doses of T 2 or T 3 for 24 h. Lipid accumulation, mRNA expression of the peroxisome proliferator-activated receptors (PPAR-a, -g, -d) the acyl-CoA oxidase (AOX), and the stearoyl CoA desaturase (SCD1), as well as fuel-stimulated O 2 consumption in intact cells, were evaluated. Lipid accumulation was associated with an increase in triacylglycerol content, PPARg mRNA expression, and a decrease in PPARd and SCD1 mRNA expression. The addition of T 2 or T 3 to lipid-overloaded cells resulted in i) reduction in lipid content; ii) downregulation of PPARa, PPARg, and AOX expression; iii) increase in PPARd expression; and iv) stimulation of mitochondrial uncoupling. These data demonstrate, for the first time, that in the hepatocyte, the lipid-lowering actions of both T 2 and T 3 are not mediated by TRs.

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“…PPARα‐ as well as PPARγ‐deficient mice are more sensitive to the development of steatohepatitis under an MCD than wild‐type mice 21, 22. Using selective PPAR agonists, it was reported that Wy‐14,643 (a PPARα agonist), GW501516 (a PPARδ agonist), and PPARγ activation by pioglitazone prevent and/or reverse MCD‐induced steatohepatitis 21, 22, 23, 24, 25. In the foz/foz model, a protective effect on steatohepatitis was observed with PPARα agonist treatment 15…”

Section: Discussionmentioning

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

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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Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARδ agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet

Cited by 221 publications

References 35 publications

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

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

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