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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

From the Departments of Medicine and Biochemistry and the Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

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) (MAPK^erk) 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 MAPK^p38, a negative regulator of MAPK^erk activity. Inhibition of MEK1/2 significantly attenuated both the naringenin- and insulin-induced decrease in apoB100 secretion demonstrating a direct link between MAPK^erk activation and apoB100 secretion. Furthermore, both compounds increased MAPK^p38 activation, and therefore inhibition of MAPK^p38 amplified thenaringenin- and insulin-induced decrease in apoB100 secretion. We conclude that MAPK^erk 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.

Abbreviations: apo, apolipoprotein; ERK, extracellular signal–regulated kinase; LDL-r, LDL receptor; LPDS, lipoprotein-deficient serum; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; MTP, microsomal triglyceride transfer protein; PI, phosphatidylinositol; SREBP, sterol regulatory element–binding protein

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