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Molecular and Cellular Biochemistry

, Volume 285, Issue 1–2, pp 35–50 | Cite as

Peroxisome proliferator-activated receptor-α selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice

  • Rai Ajit K. Srivastava
  • Ravi Jahagirdar
  • Salman Azhar
  • Somesh Sharma
  • Charles L. Bisgaier
Article

Abstract

Fenofibrate, a selective 1PPAR-α activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-α reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-α activators may be useful in the treatment of syndrome X. (Mol Cell Biochem xxx: 1–16, 2005)

Keywords

metabolic syndrome X obesity PPAR diabetes atherosclerosis LDL receptor knock out fenofibrate lipogenesis VCAM-1 

Abbreviation

PPAR

Peroxisome proliferator activated receptor

LDLr

low density lipoprotein receptor

SREBP1

Sterol response element binding protein 1

DGAT2

Diacyl glycerol acyl transferase

PEPCK

Phosphoenol pyruvate carboxy kinase

TNF-α

Tumor necrosis factor alpha

UCP

Uncoupling protein

LPL

Lipoprotein lipase

ACO

Acetyl CoA oxidase

ACC

Acetyl CoA carboxylase

FAS

Fatty acid synthase

VCAM1

Vascular cell adhesion molecule 1

HAEC

Human aortic endothelial cell

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Rai Ajit K. Srivastava
    • 1
    • 5
  • Ravi Jahagirdar
    • 1
  • Salman Azhar
    • 2
  • Somesh Sharma
    • 3
  • Charles L. Bisgaier
    • 4
  1. 1.CloneGen BiotechnologyAnn ArborUSA
  2. 2.Stanford University School of MedicinePalo AltoUSA
  3. 3.Nicholas Piramal Research CenterMumbaiIndia
  4. 4.Esperion TherapeuticsA Division of Pfizer Global Research & DevelopmentAnn ArborUSA
  5. 5.Department of AtherosclerosisBristol-Myers SquibbPenningtonUSA

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