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Journal of Lipid Research, Vol. 49, 2218-2229, October 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor^*

Emma M. Allister^2,*, Erin E. Mulvihill^2,*, P. Hugh R. Barrett, Jane Y. Edwards^*, Lindsey P. Carter^* and Murray W. Huff^1,*

^* Robarts Research Institute, Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia

^* This research was supported by grants from the Heart and Stroke Foundation of Ontario (T-5603 and PRG-5967) to M.W.H., and the National Institutes of Health (NIBIB #P41 EB-001975) to P.H.R.B. P.H.R.B is a fellow of the National Health and Medical Research Council of Australia. E.M.A. received a post-doctoral fellowship from the Heart and Stroke Foundation of Canada, and E.E.M. is the recipient of a Canada Graduate Scholarship from the Canadian Institutes for Health Research.

Published, JLR Papers in Press, June 27, 2008.

² E. M. Allister and E. E. Mulvihill contributed equally to this work.

¹ To whom correspondence should be addressed. e-mail: mhuff{at}uwo.ca

Hepatic overproduction of apolipoprotein B (apoB)-containing lipoproteins is characteristic of the dyslipidemia associated with insulin resistance. Recently, we demonstrated that the flavonoid naringenin, like insulin, decreased apoB secretion from HepG2 cells by activation of both the phosphoinositide-3-kinase (PI3-K) pathway and the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK^erk) pathway. In the present study, we determined whether naringenin-induced signaling required the insulin receptor (IR) and sensitized the cell to the effects of insulin, and whether the kinetics of apoB assembly and secretion in cells exposed to naringenin were similar to those of insulin. Immunoblot analysis revealed that insulin stimulated maximal phosphorylation of IR and IR substrate-1 after 10 min, whereas naringenin did not affect either at any time point up to 60 min. The combination of naringenin and submaximal concentrations of insulin potentiated extracellular-regulated kinase 1/2 activation and enhanced upregulation of the LDL receptor, downregulation of microsomal triglyceride transfer protein expression, and inhibition of apoB-100 secretion. Multicompartmental modeling of apoB pulse-chase studies revealed that attenuation of secreted radiolabeled apoB in naringenin- or insulin-treated cells was similar under lipoprotein-deficient or oleate-stimulated conditions. Naringenin and insulin both stimulated intracellular apoB degradation via a kinetically defined rapid pathway. Therefore, naringenin, like insulin, inhibits apoB secretion through activation of both PI3-K and MAPK^erk signaling, resulting in similar kinetics of apoB secretion. However, the mechanism for naringenin-induced signaling is independent of the IR. Naringenin represents a possible strategy for reduction of hepatic apoB secretion, particularly in the setting of insulin resistance.

Supplementary key words apolipoprotein B • citrus flavonoid: • oleate • multicompartmental modeling • kinetics • degradation • microsomal triglyceride transfer protein • LDL receptor • phosphoinositide-3-kinase • mitogen-activated protein kinase/extracellular-regulated kinase

Abbreviations: apoB, apolipoprotein B; CE, cholesteryl ester; ER, endoplasmic reticulum; ERK, extracellular-regulated kinase; FFA, free fatty acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IR, insulin receptor; IRS, insulin receptor substrate; LDLr, low-density lipoprotein receptor; LPDS, lipoprotein-deficient serum; MAPK, mitogen-activated protein kinase; MTP, microsomal triglyceride transfer protein; OA, oleic acid; PI3-K, phosphoinositide-3-kinase; PL, phospholipid; TG, triglyceride

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