PPARδ regulates glucose metabolism and insulin sensitivity

Lee, Chih‐Hao; Olson, Peter; Hevener, Andrea L.; Mehl, Isaac R.; Chong, Ling Wa; Olefsky, Jerrold M.; Gonzalez, Frank J.; Ham, Jungyeob; Kang, Heonjoong; Peters, Jeffrey M.; Evans, Ronald M.

doi:10.1073/pnas.0511253103

Cited by 448 publications

(446 citation statements)

References 35 publications

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“…Further, a PathwayAssist analysis revealed that GK is closely linked to PPARα and SREBPs [2]. Recent studies have shown that G6PDH is a target gene for both PPARα, SREBP1c, and SREBP2 in liver [50,[57][58][59]. Together, these data indicate that it is likely that GK mediates the PPP through its network partners PPARα, SREBP1c, and SREBP2.…”

Section: Discussionmentioning

confidence: 86%

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

Sriram

Rahib

et al. 2008

Molecular Genetics and Metabolism

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Glycerol kinase has several diverse activities in mammalian cells. Glycerol kinase deficiency is a complex, single-gene, inborn error of metabolism wherein no genotype-phenotype correlation has been established. Since glycerol kinase has been suggested to exhibit additional activities than glycerol phosphorylation, expression level perturbation in this enzyme may affect cellular physiology globally. To investigate this possibility, we conducted metabolic investigations of wild type and two glycerol kinase-overexpressing H4IIE rat hepatoma cell lines constructed in this study. The glycerol kinase-overexpressing cell lines exhibited a significantly higher consumption of carbon sources per cell, suggesting excess carbon expenditure. Furthermore, we quantified intracellular metabolic fluxes by employing stable isotope ( 13 C) labeling with a mathematically designed substrate mixture, gas chromatography-mass spectrometry, and comprehensive isotopomer balancing. This flux analysis revealed that the pentose phosphate pathway flux in the glycerol kinase-overexpressing cell lines was two-fold higher than that in the wild type, in addition to subtler flux changes in other pathways of carbohydrate metabolism. Furthermore, the activity and transcript level of the lipogenic enzyme glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway, were also about two-fold higher than that of the wild type; these data corroborate the flux analysis results. This study shows that glycerol kinase affects carbon metabolism globally, possibly through its additional functions, and highlights glycerol kinase's multifaceted role in cellular physiology.

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Section: Discussionmentioning

confidence: 86%

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

Sriram

Rahib

et al. 2008

Molecular Genetics and Metabolism

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“…In recent years PPARδ has emerged as a key protein in the regulation of energy metabolism by its ability to enhance fatty acid catabolism, energy uncoupling and insulin sensitivity in the liver, adipose tissue and skeletal muscle [6][7][8][9][10]36].…”

Section: Discussionmentioning

confidence: 99%

“…In skeletal muscle, overexpression of Ppard in mice increases oxidative metabolism, changes muscle fibre type towards oxidative type I fibres and improves physical endurance thereby averting obesity induced by a high-fat diet or genetically [6,7]. Additionally, a recent study of genetically modified mice provides evidence that PPARδ regulates glucose metabolism and insulin sensitivity in both skeletal muscle and the liver, interestingly indicating a subtle PPARδ-controlled change in substrate utilisation [8]. Increased Ppard expression in adipose tissue in mice is associated with reduced adiposity and lower serum lipid levels [9,10].…”

Section: Introductionmentioning

confidence: 99%

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

Grarup

Albrechtsen

et al. 2007

Diabetologia

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Aims/hypothesis Studies in animals reveal that peroxisome proliferator-activated receptor δ (PPARδ) regulates glucose metabolism and insulin sensitivity in both the liver and skeletal muscles. Moreover, PPARδ augments physical endurance and increases oxidative metabolism, thereby averting obesity. Thus, we hypothesised that common variation in the PPARD gene is associated with insulin resistance and metabolic traits. Materials and methods We studied variation in the exonic region of PPARD. Based upon the results of variant detection and information derived from the HapMap data resource, we selected common variants and tag singlenucleotide polymorphisms for genotyping in 7,495 white subjects, including 1,416 patients with type 2 diabetes. Results Fourteen nucleotide variants were identified and a total of 12 variants capturing the common variation of PPARD were genotyped. In the population-based Inter99 (ClinicalTrials.gov ID no: NCT00289237) sample we observed no robust association with homeostasis model assessment of insulin resistance (HOMA-IR), adiposity measures or fasting serum lipids. Similarly, no association with type 2 diabetes or the metabolic syndrome was found. Conclusions/interpretation Based on thorough investigation, we conclude that common variation in PPARD does not significantly affect the risk of metabolic disease in the population studied. Given the confidence intervals that were found for effect size estimates, we can effectively rule out an increase in HOMA-IR of any tag SNP above 7% per allele, assuming an additive model. Likewise, we can exclude an odds ratio of type 2 diabetes above 1.27 per allele.

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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

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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PPARδ regulates glucose metabolism and insulin sensitivity

Cited by 448 publications

References 35 publications

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

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

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