title: Oncostatin M produced in Kupffer cells in response to PGE2: possible contributor to hepatic insulin resistance and steatosis.
abstract: Hepatic insulin resistance is a major contributor to hyperglycemia in metabolic syndrome and type II diabetes. It is caused in part by the low-grade inflammation that accompanies both diseases, leading to elevated local and circulating levels of cytokines and cyclooxygenase (COX) products such as prostaglandin E(2) (PGE(2)). In a recent study, PGE(2) produced in Kupffer cells attenuated insulin-dependent glucose utilization by interrupting the intracellular signal chain downstream of the insulin receptor in hepatocytes. In addition to directly affecting insulin signaling in hepatocytes, PGE(2) in the liver might affect insulin resistance by modulating cytokine production in non-parenchymal cells. In accordance with this hypothesis, PGE(2) stimulated oncostatin M (OSM) production by Kupffer cells. OSM in turn attenuated insulin-dependent Akt activation and, as a downstream target, glucokinase induction in hepatocytes, most likely by inducing suppressor of cytokine signaling 3 (SOCS3). In addition, it inhibited the expression of key enzymes of hepatic lipid metabolism. COX-2 and OSM mRNA were induced early in the course of the development of non-alcoholic steatohepatitis (NASH) in mice. Thus, induction of OSM production in Kupffer cells by an autocrine PGE(2)-dependent feed-forward loop may be an additional, thus far unrecognized, mechanism contributing to hepatic insulin resistance and the development of NASH.
authors.affiliation: Universität Potsdam, Institut für Ernährungswissenschaft, Biochemie der Ernährung, Nuthetal, Germany.
authors.forename: Janin
authors.initials: J
authors.lastname: Henkel
authors.forename: Daniela
authors.initials: D
authors.lastname: Gärtner
authors.forename: Christoph
authors.initials: C
authors.lastname: Dorn
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Nancy
authors.initials: N
authors.lastname: Schanze
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Elz
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Püschel
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000502:physiology*; D005234:Fatty Liver / Q000503:physiopathology*; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053683:Oncostatin M / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D053683:Oncostatin M; D015232:Dinoprostone