Insulin-like effects of naringenin on inhibition of apolipoprotein B secretion from HepG2 cells occur via MAPK/ERK signaling and are independent of insulin receptor activation

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

Medicine and Biochemistry, Robarts Research Institute, London, Ontario N6A 5K8

Corresponding Author: 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) and the mitogen activated protein/extracellular regulated kinase (MAPK^erk). In the present study, we determined whether naringenin-induced signaling required the insulin receptor, sensitised the cell to the effects of insulin and if the kinetics of apoB assembly and secretion in cells exposed to naringenin were similar to insulin. Immunoblot analysis revealed that insulin stimulated maximal insulin receptor phosphorylation and insulin receptor substrate-1 after 10 min whereas naringenin did not affect either at any time point up to 60 min. The combination of naringenin and sub-maximal concentrations of insulin potentiated ERK1/2 activation, and enhanced upregulation of the low-density lipoprotein receptor, downregulation of microsomal triglyceride transfer protein expression and inhibition of apoB100 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 insulin receptor. Naringenin represents a possible strategy for reduction of hepatic apoB secretion, particularly in the setting of insulin resistance.

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