%0 Generic
%A Chichelnitskiy, Evgeny
%D 2009
%F heidok:9447
%K Metabolism, Inflammation, Interference, Gluconeogenesis
%R 10.11588/heidok.00009447
%T HORMONAL-INFLAMMATORY INTERFERENCE IN THE CONTROL OF DE NOVO GLUCOSE PRODUCTION BY THE LIVER
%U https://archiv.ub.uni-heidelberg.de/volltextserver/9447/
%X Abstract In mammals the maintenance of an appropriate glucose level in the blood is a prerequisite of good health and survival. The blockade of stress compensatory de novo glucose production by the liver, gluconeogenesis, during acute inflammation is one of the major characteristics of the aberrant metabolic state and a reason of death in septic patients. Interference with hormone signaling and the subsequent suppression of key rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) through pro-inflammatory mediators importantly contribute to severe hypoglycemia in sepsis. However, the molecular mechanisms of aberrant PEPCK gene regulation under these conditions in vivo remain largely unknown.  In the present study we report the generation of a liver-specific adenoviral reporter system for the identification of dysfunctional gene cis-regulatory promoter elements under pathological conditions in mice. By employing in vivo promoter reporter technology, the glucocorticoid response unit (GRU) and the cAMP-response element (CRE) of the PEPCK gene were identified as critical promoter target sites of pro-inflammatory signaling. The disruption of the synergistic function of these two promoter elements was found to mediate PEPCK gene inhibition under septic conditions. Furthermore, the expression of nuclear receptor co-factor PGC-1α, the molecular mediator of GRU/CRE synergism on the PEPCK promoter, was found to be specifically repressed in septic liver. The depletion of endogenous PGC-1α with RNAi blunts the inflammatory suppressive effect on the PEPCK gene in cytokine-exposed primary hepatocytes while PGC-1α over-expression restores PEPCK expression under the same conditions.   These results provide an in vivo mechanism involved in the suppression of the key gluconeogenic gene PEPCK in septic mouse.  The maintenance of PGC-1α activity might represent an attractive therapeutic defense for the rescue of gluconeogenic program repression and hypoglycemia in septic patients.