title: Free fatty acids shift insulin-induced hepatocyte proliferation towards CD95-dependent apoptosis.
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.
authors.affiliation: From the Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Sommerfeld
authors.affiliation: From the Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Reinehr
authors.affiliation: From the Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany haeussin@uni-duesseldorf.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D017382:Reactive Oxygen Species; D019014:fas Receptor; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases
keywords: CD95; apoptosis; c-Jun N-terminal kinase (JNK); epidermal growth factor receptor (EGFR); fatty acid; insulin