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.