The vicious circle of prostaglandin- and cytokine-dependent hepatic insulin resistance: a key role of prostaglandin E2

Background & aims: Hepatic insulin resistance and the ensuing impairment of hepatic glucose metabolism is a major contributor to hyperglycemia in metabolic syndrome and type II diabetes. In patients suffering from these ailments, a low-grade inflammation prevails besides an impaired fatty acid handling. Both contribute to the development of insulin resistance. While the impact of fatty acids and pro-inflammatory cytokines on the insulin signalling cascade are well established, the role of small lipid mediators like prostaglandins, which are released from resident liver macrophages and infiltrating immune cells, is not well characterized. The current study addressed this question. Material & Methods: Male C57BL/6 mice were fed chow or a modified western diet containing high fat, cholate and cholesterol as well as high fructose in drinking water. Human macrophages (cell line U937) or primary mouse macrophages were incubated with LPS or PGE2. Human or primary rat hepatocytes were pre incubated either with PGE2, IL 6, OSM or with conditioned media of PGE2-stimulated macrophages and subsequently stimulated with insulin. Gene expression and activation of insulin- and cytokine signalling were quantified by westernblot and RT qPCR. Results: Hepatic expression of key enzymes in prostaglandin E2 (PGE2) formation, namely cyclooxygenase 2 (COX2) and microsomal PGE2 synthase 1 (mPGES1), was induced 2 to 4-fold in mice fed a modified western diet suggesting an enhanced capacity for local PGE2 formation in these mice. In primary human and rat hepatocytes PGE2 interrupted Akt-dependent insulin signalling. It enhanced hepatic lipid accumulation by inhibiting hepatic lipid utilisation. The underlying molecular mechanisms involved a PGE2-mediated sustained ERK1/2 kinase activation, which resulted in an inhibitory serine phosphorylation of IRS. PGE2 acted synergistically with IL-6 or OSM, which attenuated insulin signalling by inducing SOCS3. In mouse and human macrophages the production of these cytokines was stimulated by PGE2. While PGE2 enhanced IL-6, OSM and IL-1β formation, TNFα expression remained unchanged or was reduced. Cytokines and PGE2 induced the PGE2-generating enzymes COX2 and mPGES1. Conditioned medium of murine or human macrophages treated with PGE2 stimulated the phosphorylation of STAT3 and induced SOCS3 in hepatocytes, while insulin-dependent glucokinase induction was attenuated. These effects were abolished after parallel incubation with an OSM-neutralizing antibody or treatment of macrophages with the COX2-inhibitor indomethacin. Conclusion: In addition to directly interrupting insulin signalling pathway in hepatocytes, PGE2 may further impair hepatic insulin sensitivity in an autocrine feed-forward vicious cycle by inducing cytokines like OSM and its own synthesis in macrophages. The enzymes involved in the PGE2 synthesis might therefore be potential new drug targets for the treatment of hepatic insulin resistance. Corresponding author: Henkel, Janin E-Mail: jhenkel@uni-potsdam.de