Insulin is known to induce hepatocyte swelling, which triggers via
integrins and
c-Src kinase an activation of the
epidermal growth factor receptor (EGFR) and subsequent cell proliferation (1).
Free fatty acids (FFAs) are known to induce lipoapoptosis in liver cells in a c-Jun-NH2-terminal
kinase (JNK)-dependent, but
death receptor-independent way (2). As non-
alcoholic steatohepatitis (NASH) is associated with
hyperinsulinemia and increased FFA-blood levels, the interplay between
insulin and FFA was studied with regard to hepatocyte proliferation and apoptosis in isolated rat and mouse hepatocytes. Saturated long chain FFAs induced apoptosis and JNK activation in primary rat hepatocytes, but did not activate the CD95 (Fas, APO-1) system, whereas
insulin triggered EGFR activation and hepatocyte proliferation. Coadministration of
insulin and FFAs, however, abolished hepatocyte proliferation and triggered CD95-dependent apoptosis due to a JNK-dependent association of the activated EGFR with CD95, subsequent CD95
tyrosine phosphorylation and formation of the death-inducing signaling complex (DISC). JNK inhibition restored the proliferative
insulin effect in presence of FFAs and prevented EGFR/CD95 association, CD95
tyrosine phosphorylation and DISC formation. Likewise, in presence of FFAs
insulin increased apoptosis in hepatocytes from wild type but not from Alb-Cre-FAS(fl/fl) mice, which lack functional CD95. It is concluded that FFAs can shift
insulin-induced hepatocyte proliferation toward hepatocyte apoptosis by triggering a JNK signal, which allows activated EGFR to associate with CD95 and to trigger CD95-dependent apoptosis. Such phenomena may contribute to the pathogenesis of NASH.