Naringenin prevents dyslipidemia, apoB overproduction and hyperinsulinemia in LDL-receptor null mice with diet-induced insulin resistance.

  1. Erin E. Mulvihill1,2,
  2. Emma M. Allister1,
  3. Brian G. Sutherland1,
  4. Dawn E. Telford1,3,
  5. Cynthia G. Sawyez1,3,
  6. Jane Y. Edwards1,3,
  7. Janet M. Markle1,
  8. Robert A. Hegele1,2,3,4 and
  9. Murray W. Huff (mhuff{at}uwo.ca)1,2,3
  1. 1 Vascular Biology, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8
  2. 2Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada, N6A 5K8
  3. 3Department of Medicine, The University of Western Ontario, London, Ontario, Canada, N6A 5K8
  4. 4 Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8

    Abstract

    Objective: The global epidemic of metabolic syndrome and its complications demand rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin has lipid-lowering properties and inhibits very low density lipoprotein (VLDL) secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance, in vivo.

    Research Methods and Design: Low density lipoprotein receptor null (Ldlr−/−) mice fed a high fat (western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant and obese. Four groups of mice (chow, western and western plus 1% or 3%, w/w naringenin) were fed ad libitum for 4 weeks. Very low density lipoprotein (VLDL) production and parameters of insulin and glucose tolerance were determined.

    Results: We report that naringenin treatment of Ldlr−/− mice fed a western diet, corrected VLDL overproduction, ameliorated hepatic steatosis and attenuated dyslipidemia, without affecting caloric intake or fat absorption. Naringenin: 1) increased hepatic fatty-acid oxidation through a PPARγ coactivator 1 alpha, (PGC1α)/PPARα-mediated transcription program; 2) prevented SREBP1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis, 4) reduced both VLDL-derived and endogenously synthesized fatty acid preventing muscle triglyceride accumulation; 5) improved overall insulin sensitivity and glucose tolerance.

    Conclusion: Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome.

    Footnotes

      • Received April 29, 2009.
      • Accepted June 22, 2009.

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