Proposed signaling pathways for naringenin- and insulin-mediated increases in LDL-r expression, decreases in MTP expression,
and inhibition of apoB100 secretion in HepG2 cells. Naringenin and insulin increase (A) PI 3-kinase activity and (B) ERK1/2 phosphorylation via MEK1/2 activation. Naringenin activates both pathways independent of IRS-1/2 phosphorylation
(pY). Naringenin may bypass the insulin receptor by activating the GTPase Ras. Naringenin and insulin activate MAPKp38, which attenuates MEK1/2 activity; however, MEK1/2 activation predominates, resulting in increased ERK1/2 phosphorylation.