Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.

Département d'Athérosclérose, Institut Pasteur de Lille, INSERM U545, and Université de Lille 2, Lille, France.
Journal of Clinical Investigation (Impact Factor: 13.77). 04/2006; 116(3):571-80. DOI: 10.1172/JCI27989
Source: PubMed

ABSTRACT PPARalpha is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARalpha also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARalpha help explain the clinical actions of fibrates, synthetic PPARalpha agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARalpha in humans, recent findings have revealed potential adverse effects of PPARalpha action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARalpha in metabolic diseases and their associated vascular pathologies.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The +294T/C polymorphism in the peroxisome proliferator-activated receptor delta (PPARD) gene is associated with hyperlipidemia in several younger populations, but results are still inconsistence across ethnic groups and its possible impact on the lipid profiles of long-lived individuals remains unexploited. Here, we aimed to evaluate the possible correlation between PPARD +294T/C and serum lipid levels in a long-lived population in Bama, a region known for longevity situated in Guangxi, China. Methods Genotyping of PPARD +294T/C polymorphism was conducted in 505 long-lived inhabitants (aged 90 and above, long-lived group, LG) and 468 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Results No difference in allelic and genotypic frequencies was found between the two groups (P > 0.05). However, C-allele and C-genotype (TC and CC) were significantly more frequent in the females of non-LG than were LG after sex stratification. CC carriers exhibited higher LDL-C level in LG (P < 0.05) but lower TC, TG and LDL-C in non-LG (P < 0.05 for each) than TT carriers; C allele carriers (TC/CC) in LG exhibited higher TC, TG, and LDL-C levels as compared with the same genotype and the same lipid parameter in non-LG (P < 0.05 for each). LDL-C in LG was correlated with genotypes while TC, TG, and LDL-C in non-LG were correlated with genotypes (P < 0.05-0.001). Conclusion Our results suggest that there were different impact patterns of PPARD +294T/C polymorphism on lipid profiles between long-lived cohort and average population in Bama area and this may be one of the genetic bases of its longevity.
    Lipids in Health and Disease 03/2015; 14(1). DOI:10.1186/s12944-015-0016-3 · 2.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of obesity-related diabetes is increasing world-wide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure, curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in a diet-induced obese mice. The peptapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetylCoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes GLP-1(32-36)amide activated AMP kinase and inhibited acetyl CoA carboxylase suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 04/2015; DOI:10.2337/db14-1708 · 8.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, much evidence suggested that vitamin D plays an important role in decreasing the risk of type 2 diabetes. The purpose of this study was to investigate whether 1, 25 (OH) 2D3 can modulate inflammation and lipid metabolism in type 2 diabetic rat liver. Type 2 diabetes was induced in SD rat with high-fat and high-sugar diets and multiple low-dose streptozotocin. The levels of serum calcium, phosphorus, glucose, TC, TG, AST, ALT and hepatic TG were determined. H & E staining were performed to assess the effects of vitamin D treatment on pathological changes in the liver tissues. Immunohistology, real-time PCR and Western blot were used to evaluate the expressions of NF-κ B, MCP-1, ICAM-1, TGF-β1, PPAR-α and CPT-1. The administration of 1, 25 (OH) 2D3 reduced liver weight. Compared to DM rats, 1, 25 (OH) 2D3-treated DM rats had lower liver weight. Moreover, compared to healthy or 1, 25 (OH) 2D3-treated DM rats, DM rats had increased hepatic transcription factors (NF-κ B), monocyte chemoattractant protein -1 (MCP-1), intercellular adhesion molecule -1 (ICAM-1), transforming growth factor-β1 (TGF-β1) expressions, but had fewer hepatic PPAR- α and CPT-1 expressions. 1, 25 (OH) 2D3 significantly modulated the liver inflammation and lipid metabolism in diabetic rat models, which may be caused by its regulations on hepatic signaling NF-κ B pathway and PPAR- α.
    Lipids in Health and Disease 04/2015; 14(1):31. DOI:10.1186/s12944-015-0030-5 · 2.31 Impact Factor