Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock

Tamara Merz, Josef A. Vogt, Ulrich Wachter, Enrico Calzia, Csaba Szabo, Rui Wang, Peter Radermacher, Oscar McCook

Cystathionine-γ-lyase (CSE) was shown to have a regulatory role in glucose metabolism. Circulatory shock can induce metabolic stress, thereby leading to hyperglycemia and mitochondrial dysfunction. In vitro data suggest an effect of high glucose on CSE expression. Therefore, the aim of this study was to investigate the effects of hyperglycemia on CSE expression in resuscitated murine septic shock. Normo- (80-150 mg/dl) and hyperglycemic (>200 mg/dl) male C57/BL6J mice (n = 5-6 per group) underwent cecal ligation and puncture (CLP)-induced polymicrobial sepsis or sham procedure (n = 6 per group) and, 15 h afterwards, were anesthetized again, surgically instrumented and received intensive care treatment, including antibiotics, lung protective mechanical ventilation, circulatory support, and intravenous (i.v.) glucose infusion (50% as stable-isotope labeled 1,2,3,4,5,6-(13)C6 glucose). Blood and breath gas were sampled hourly to quantify parameters of glucose metabolism. 5 h later, mice were sacrificed and organs were harvested. The liver mitochondrial respiratory activity was determined via high resolution respirometry; CSE, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and adipocyte differentiation-related protein (ADRP) expression was immunohistochemically investigated. In sepsis combined with hyperglycemia the least CSE and PGC1α expression could be detected, along with reduced mitochondrial respiratory activity, and enhanced ADRP expression, a marker of lipid droplet formation, in the liver. A novel in vivo finding is the CSE translocation from the cytosol to the nucleus triggered by metabolic stress. A relationship between CSE and glucose metabolism was established, which, when dysregulated, may contribute to fatty liver disease and hepatic steatosis.