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PMID: 11306606 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice.

The Journal of clinical investigation ·Vol. 107 ·No. 8 ·2001-04-00 ·Pages 1025-34

Tordjman K, Bernal-Mizrachi C, Zemany L, Weng S, Feng C, Zhang F, Leone TC, Coleman T, Kelly DP, Semenkovich CF

Abstract

PPARalpha is a ligand-dependent transcription factor expressed at high levels in the liver. Its activation by the drug gemfibrozil reduces clinical events in humans with established atherosclerosis, but the underlying mechanisms are incompletely defined. To clarify the role of PPARalpha in vascular disease, we crossed PPARalpha-null mice with apoE-null mice to determine if the genetic absence of PPARalpha affects vascular disease in a robust atherosclerosis model. On a high-fat diet, concentrations of atherogenic lipoproteins were higher in PPARalpha(-/-)apoE(-/-) than in PPARalpha(+/+)apoE(-/-) mice, due to increased VLDL production. However, en face atherosclerotic lesion areas at the aortic arch, thoracic aorta, and abdominal aorta were less in PPARalpha-null animals of both sexes after 6 and 10 weeks of high-fat feeding. Despite gaining as much or more weight than their PPARalpha(+/+)apoE(-/-) littermates, PPARalpha(-/-)apoE(-/-) mice had lower fasting levels of glucose and insulin. PPARalpha-null animals had greater suppression of endogenous glucose production in hyperinsulinemic clamp experiments, reflecting less insulin resistance in the absence of PPARalpha. PPARalpha(-/-)apoE(-/-) mice also had lower blood pressures than their PPARalpha(+/+)apoE(-/-) littermates after high-fat feeding. These results suggest that PPARalpha may participate in the pathogenesis of diet-induced insulin resistance and atherosclerosis.

MeSH Terms
Animals Aorta/metabolism Apolipoproteins E/genetics,metabolism,physiology Arteriosclerosis/metabolism,pathology Blood Pressure CD36 Antigens/genetics Chemokine CCL2/genetics Dietary Fats/metabolism Female Gene Expression Glucose/metabolism Insulin Resistance Lipoprotein Lipase/metabolism Lipoproteins/metabolism Macrophages/metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Pyrimidines/metabolism Receptors, Cytoplasmic and Nuclear/genetics,metabolism,physiology Transcription Factors/genetics,metabolism,physiology
Chemicals
Apolipoproteins E CD36 Antigens Chemokine CCL2 Dietary Fats Lipoproteins Pyrimidines Receptors, Cytoplasmic and Nuclear Transcription Factors pirinixic acid Lipoprotein Lipase Glucose
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Tordjman K
Department of Medicine and the Center for Cardiovascular Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Bernal-Mizrachi C
Zemany L
Weng S
Feng C
Zhang F
Leone T C
Coleman T
Kelly D P
Semenkovich C F
References (53)
53 references, click to expand
  1. Peroxisome proliferator activated receptor-alpha expression in human liver.
    Mol Pharmacol. 1998 Jan;53(1):14-22 PMID: 9443928
  2. Effect of streptozotocin-induced hyperglycemia on lipid profiles, formation of advanced glycation endproducts in lesions, and extent of atherosclerosis in LDL receptor-deficient mice.
    Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2250-6 PMID: 9351397
  3. C57BL/6 mice fed high fat diets as models for diabetes-accelerated atherosclerosis.
    Atherosclerosis. 1998 Jan;136(1):17-24 PMID: 9544727
  4. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL.
    Cell. 1998 Apr 17;93(2):241-52 PMID: 9568716
  5. Effects of heterozygous lipoprotein lipase deficiency on diet-induced atherosclerosis in mice.
    J Lipid Res. 1998 Jun;39(6):1141-51 PMID: 9643345
  6. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.
    Mol Cell. 1998 Aug;2(2):275-81 PMID: 9734366
  7. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.
    Nat Med. 1998 Sep;4(9):1025-31 PMID: 9734395
  8. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor alpha- deficient mice.
    J Clin Invest. 1998 Sep 15;102(6):1083-91 PMID: 9739042
  9. Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis.
    J Biol Chem. 1998 Nov 6;273(45):29577-85 PMID: 9792666
  10. Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice.
    J Biol Chem. 1998 Nov 13;273(46):30427-34 PMID: 9804809
  11. Altered nuclear protein binding to the first intron of the renin gene of the spontaneously hypertensive rat.
    Clin Exp Hypertens. 1998 Nov;20(8):817-32 PMID: 9817604
  12. Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene.
    J Biol Chem. 1999 Feb 12;274(7):3970-7 PMID: 9933587
  13. Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging.
    Curr Opin Lipidol. 1999 Apr;10(2):151-9 PMID: 10327283
  14. Regulation of NO-elicited pulmonary artery relaxation and guanylate cyclase activation by NADH oxidase and SOD.
    Am J Physiol. 1999 May;276(5 Pt 2):H1535-42 PMID: 10330236
  15. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.
    J Clin Invest. 1999 Jun;103(11):1489-98 PMID: 10359558
  16. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo.
    J Clin Invest. 1999 Jun;103(12):1697-705 PMID: 10377176
  17. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
    N Engl J Med. 1999 Aug 5;341(6):410-8 PMID: 10438259
  18. Relative hypoglycemia and hyperinsulinemia in mice with heterozygous lipoprotein lipase (LPL) deficiency. Islet LPL regulates insulin secretion.
    J Biol Chem. 1999 Sep 24;274(39):27426-32 PMID: 10488074
  19. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension.
    Nature. 1999 Dec 23-30;402(6764):880-3 PMID: 10622252
  20. Enhanced atherosclerosis and kidney dysfunction in eNOS(-/-)Apoe(-/-) mice are ameliorated by enalapril treatment.
    J Clin Invest. 2000 Feb;105(4):451-8 PMID: 10683374
  21. Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1.
    Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):846-52 PMID: 10712412
  22. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.
    J Clin Invest. 2000 Apr;105(8):1049-56 PMID: 10772649
  23. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors.
    Circulation. 2000 May 23;101(20):2411-7 PMID: 10821819
  24. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.
    J Biol Chem. 2000 Jun 2;275(22):16638-42 PMID: 10828060
  25. Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia.
    J Lipid Res. 2000 Jun;41(6):945-52 PMID: 10828087
  26. Roles of PPARs in health and disease.
    Nature. 2000 May 25;405(6785):421-4 PMID: 10839530
  27. Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.
    Diabetologia. 2000 May;43(5):673-80 PMID: 10855543
  28. The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants.
    Pharmacogenetics. 2000 Jun;10(4):321-33 PMID: 10862523
  29. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice.
    J Biol Chem. 2000 Aug 25;275(34):26293-9 PMID: 10858435
  30. Acute modulation of endothelial Akt/PKB activity alters nitric oxide-dependent vasomotor activity in vivo.
    J Clin Invest. 2000 Aug;106(4):493-9 PMID: 10953024
  31. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.
    J Clin Invest. 2000 Aug;106(4):523-31 PMID: 10953027
  32. Role of macrophage-derived lipoprotein lipase in lipoprotein metabolism and atherosclerosis.
    Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E53-62 PMID: 10978269
  33. Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells.
    Circ Res. 2000 Sep 15;87(6):516-21 PMID: 10988245
  34. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice.
    Nat Med. 2000 Oct;6(10):1115-20 PMID: 11017142
  35. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk).
    BMJ. 2001 Jan 6;322(7277):15-8 PMID: 11141143
  36. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
    Nat Med. 2001 Jan;7(1):53-8 PMID: 11135616
  37. Control mechanisms of gluconeogenesis and ketogenesis. I. Effects of oleate on gluconeogenesis in perfused rat liver.
    J Biol Chem. 1969 Sep 10;244(17):4607-16 PMID: 4390110
  38. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.
    J Clin Invest. 1990 Jun;85(6):1844-52 PMID: 2189893
  39. Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus.
    Diabetes Care. 1992 Jun;15(6):773-84 PMID: 1600836
  40. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice.
    J Clin Invest. 1994 Aug;94(2):899-903 PMID: 8040345
  41. Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption.
    J Clin Invest. 1994 Sep;94(3):937-45 PMID: 8083379
  42. Exercise induces human lipoprotein lipase gene expression in skeletal muscle but not adipose tissue.
    Am J Physiol. 1995 Feb;268(2 Pt 1):E229-36 PMID: 7864098
  43. COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity.
    J Biol Chem. 1995 May 26;270(21):12518-25 PMID: 7759497
  44. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.
    Mol Cell Biol. 1995 Jun;15(6):3012-22 PMID: 7539101
  45. Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter.
    J Biol Chem. 1995 Aug 18;270(33):19269-76 PMID: 7642600
  46. Regulation of guinea pig very low density lipoprotein secretion rates by dietary fat saturation.
    J Lipid Res. 1995 Jun;36(6):1188-98 PMID: 7665997
  47. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.
    Endocrinology. 1996 Jan;137(1):354-66 PMID: 8536636
  48. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators.
    Circulation. 1996 May 15;93(10):1809-17 PMID: 8635260
  49. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.
    J Clin Invest. 1995 Dec;96(6):2555-68 PMID: 8675619
  50. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene.
    EMBO J. 1996 Oct 1;15(19):5336-48 PMID: 8895578
  51. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.
    J Clin Invest. 1997 Sep 1;100(5):1230-9 PMID: 9276741
  52. Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice.
    J Biol Chem. 1997 Oct 24;272(43):27307-12 PMID: 9341179
  53. Fibrinogen deficiency is compatible with the development of atherosclerosis in mice.
    J Clin Invest. 1998 Mar 1;101(5):1184-94 PMID: 9486990
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI11497
Published
2001-04-00
Pages
1025-34
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC199556
Subset
IM
Grants
NHLBI NIH HHS · R01 HL058427 · United States
NIDDK NIH HHS · DK20579 · United States
NIDDK NIH HHS · P30 DK056341 · United States
NHLBI NIH HHS · HL-58427 · United States
NIDDK NIH HHS · P60 DK020579 · United States
NIDDK NIH HHS · DK-53198 · United States
NIDDK NIH HHS · P30 DK020579 · United States
External Links
PubMed source DOI: 10.1172/JCI11497 PMC Full Text View journal details
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