Roles of PPARs in NAFLD: Potential therapeutic targets

Tailleux, Anne; Wouters, Kristiaan; Staels, Bart

doi:10.1016/j.bbalip.2011.10.016

Cited by 237 publications

(217 citation statements)

References 145 publications

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“…We observed a striking reduction in mRNA for both Ppar␥ and its target gene Cd36 (fatty acid translocase) in Plin2-null animals on both diets. It has previously been shown that PPAR␥ and CD36 are up-regulated in the liver during obesity, insulin resistance, and NAFLD (65,66). It is possible that Plin2-null animals experience decreased uptake of free fatty acids from the periphery.…”

Section: Journal Of Biological Chemistry 24241mentioning

confidence: 99%

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Libby¹,

Bales²,

Orlicky

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanPerilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in -3 and -6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease.

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Section: Journal Of Biological Chemistry 24241mentioning

confidence: 99%

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Libby¹,

Bales²,

Orlicky

et al. 2016

Journal of Biological Chemistry

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“…The PPARα isoform, which is highly expressed in hepatocytes, controls fatty acid transport and β‐oxidation and dampens the inflammatory response 7, 8. 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

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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“…More surprisingly, the corepressor NCoR is dismissed at concentrations below the measured K d for PPARγ. However, these compounds appear not to be totally selective for PPARγ and display affinities, albeit approximately 2-log lower, for PPARα and PPARβ/δ, PPAR family members controlling, notably, fatty acid oxidation (22). However, the authors did not report on the efficacy of PPARα and PPARβ/δ activation.…”

Section: Amorfrutinsmentioning

confidence: 71%

“…Furthermore, liver steatosis was decreased upon amorfrutin treatment, but, as mentioned earlier, the authors could not exclude that this response was caused by the low affinity (but unknown efficacy) on PPARα activity (22). From a mechanistic point of view, cdk5-induced PPARγ phosphorylation, an NCoR-dependent process (23) reported to reprogram PPARγ transcription activity (20), was inhibited by rosiglitazone and amorfrutin in adipose tissues of high-fat diet-fed mice, a mechanism that could thus contribute to the antidiabetic activity of this compound.…”

Section: Amorfrutinsmentioning

confidence: 85%