Free fatty acids shift insulin-induced hepatocyte proliferation towards CD95-dependent apoptosis
Authors: Roland Reinehr
Annika Sommerfeld
Dieter H√§ussinger
Journal: Journal of Biological Chemistry (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: CD95; apoptosis; c-Jun N-terminal kinase (JNK); epidermal growth factor receptor (EGFR); fatty acid
Affiliations: From the Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University D√ºsseldorf, 40225 D√ºsseldorf, Germany., From the Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University D√ºsseldorf, 40225 D√ºsseldorf, Germany .

Abstract:  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. 

Retracted: No

PubPeer comments:
 2020 correction. https: www.jbc.org content 295 9 2885.short In Fig. 2A, the insulin P-EGFR-Y1173 and insulin+C8 P-EGFR-Y845 immunoblots are duplicated. The mishap occurred in 2014, and the reason for this could not be identified due to difficulties in reconstructing the experimental documentation. The authors state that the corresponding statistics for n = 3 are given in Fig. 2B, showing that the result of the experiment is not affected by the incorrect presentation of the exemplary immunoblot. The authors regret any problems that this error may have caused. , 
 The authors could not able to identify which blot was duplicated. Not sure how this does not change the statistics presented in panel B. How can one trust these results when the wrong blot was not identified and replaced along with the matching statistical analysis? I wonder how the journal allowed this kind of correction. Where nothing is replaced and just had to trust the authors statement and take it for granted. Is this the same path going forward?  ,