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Aggravation by prostaglandin E 2 of interleukin‐6‐dependent insulin resistance in hepatocytes
Author(s) -
Henkel Janin,
NeuschäferRube Frank,
PatheNeuschäferRube Andrea,
Püschel Gerhard P.
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23064
Subject(s) - insulin receptor substrate , insulin receptor , insulin resistance , medicine , endocrinology , insulin , protein kinase b , irs2 , irs1 , autophosphorylation , biology , glycogen synthase , socs3 , phosphorylation , protein kinase a , microbiology and biotechnology , stat3
Hepatic insulin resistance is a major contributor to fasting hyperglycemia in patients with metabolic syndrome and type 2 diabetes. Circumstantial evidence suggests that cyclooxygenase products in addition to cytokines might contribute to insulin resistance. However, direct evidence for a role of prostaglandins in the development of hepatic insulin resistance is lacking. Therefore, the impact of prostaglandin E 2 (PGE 2 ) alone and in combination with interleukin‐6 (IL‐6) on insulin signaling was studied in primary hepatocyte cultures. Rat hepatocytes were incubated with IL‐6 and/or PGE 2 and subsequently with insulin. Glycogen synthesis was monitored by radiochemical analysis; the activation state of proteins of the insulin receptor signal chain was analyzed by western blot with phosphospecific antibodies. In hepatocytes, insulin‐stimulated glycogen synthesis and insulin‐dependent phosphorylation of Akt‐kinase were attenuated synergistically by prior incubation with IL‐6 and/or PGE 2 while insulin receptor autophosphorylation was barely affected. IL‐6 but not PGE 2 induced suppressors of cytokine signaling (SOCS3). PGE 2 but not IL‐6 activated extracellular signal‐regulated kinase 1/2 (ERK1/2) persistently. Inhibition of ERK1/2 activation by PD98059 abolished the PGE 2 ‐dependent but not the IL‐6‐dependent attenuation of insulin signaling. In HepG2 cells expressing a recombinant EP3‐receptor, PGE 2 pre‐incubation activated ERK1/2, caused a serine phosphorylation of insulin receptor substrate 1 (IRS1), and reduced the insulin‐dependent Akt‐phosphorylation. Conclusion: PGE 2 might contribute to hepatic insulin resistance via an EP3‐receptor‐dependent ERK1/2 activation resulting in a serine phosphorylation of insulin receptor substrate, thereby preventing an insulin‐dependent activation of Akt and glycogen synthesis. Since different molecular mechanisms appear to be employed, PGE 2 may synergize with IL‐6, which interrupted the insulin receptor signal chain, principally by an induction of SOCS, namely SOCS3. (H EPATOLOGY 2009.)