TY  - JOUR
A1  - Henkel, Janin
A1  - Gärtner, Daniela
A1  - Dorn, Christoph
A1  - Hellerbrand, Claus
A1  - Schanze, Nancy
A1  - Elz, Sheila R.
A1  - Püschel, Gerhard Paul
T1  - Oncostatin M produced in Kupffer cells in response to PGE(2) possible contributor to hepatic insulin resistance and steatosis
JF  - Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology
N2  - 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.
KW  - cyclooxygenase
KW  - cytokine
KW  - hepatic steatosis
KW  - NASH
KW  - suppressor of cytokine signaling (SOCS)
KW  - type II diabetes (T2DM)
Y1  - 2011
U6  - https://doi.org/10.1038/labinvest.2011.47
SN  - 0023-6837
VL  - 91
IS  - 7
SP  - 1107
EP  - 1117
PB  - Nature Publ. Group
CY  - New York
ER  -