Inhibition of Microsomal Triglyceride Transfer Protein Expression and Apolipoprotein B100 Secretion by the Citrus Flavonoid Naringenin and by Insulin Involves Activation of the Mitogen-Activated Protein Kinase Pathway in Hepatocytes

  1. Emma M. Allister,
  2. Nica M. Borradaile,
  3. Jane Y. Edwards and
  4. Murray W. Huff
  1. From the Departments of Medicine and Biochemistry and the Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
  1. Address correspondence and reprint requests to Dr. Murray W. Huff, Robarts Research Institute, 4-16, 100 Perth Dr., London, Ontario, Canada, N6A 5K8. E-mail: mhuff{at}uwo.ca

Abstract

Microsomal triglyceride transfer protein (MTP) is necessary for hepatocyte assembly and secretion of apolipoprotein (apo)B100-containing lipoproteins. The citrus flavonoid naringenin, like insulin, decreased MTP expression in HepG2 cells, resulting in inhibition of apoB100 secretion; however, the mechanism for naringenin is independent of insulin receptor substrate-1/2. Recently, it was reported that insulin decreased MTP expression in HepG2 cells via the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) (MAPKerk) pathway. We hypothesized that naringenin acts via a similar mechanism. Inhibition of MAPK kinase (MEK) 1/2 in HepG2 cells significantly attenuated the naringenin- and insulin-induced reduction in MTP expression. Both naringenin and insulin increased ERK1/2 phosphorylation, which was completely inhibited by MEK1/2 inhibition and enhanced by inhibition of MAPKp38, a negative regulator of MAPKerk activity. Inhibition of MEK1/2 significantly attenuated both the naringenin- and insulin-induced decrease in apoB100 secretion demonstrating a direct link between MAPKerk activation and apoB100 secretion. Furthermore, both compounds increased MAPKp38 activation, and therefore inhibition of MAPKp38 amplified thenaringenin- and insulin-induced decrease in apoB100 secretion. We conclude that MAPKerk signaling in hepatocytes is critical for inhibition of apoB100 secretion by naringenin and insulin. Therefore, naringenin may prove useful for activating insulin-signaling pathways important for regulation of hepatocyte lipid homeostasis.

Footnotes

  • N.M.B. is currently affiliated with the Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 10, 2005.
    • Received August 27, 2004.
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