Andrea Romani
Case Western Reserve University, USA
Title: Mg2+ deficiency results in increased intra-hepatic cortisol production through the H6PD/11- β-HSD1 machinery: Role of NF-kB and inflammatory cytokines
Biography
Biography: Andrea Romani
Abstract
Tissue and serum Mg2+ defi ciency have been observed in several endocrine pathologies including diabetes and metabolic syndrome, but it is still undefi ned to which extent an altered Mg2+ homeostasis contributes to the onset of these pathologies and/or their complications. In the present study, we report that Mg2+ defi cient hepatocyte exhibit an increased entry of G6P into the endoplasmic reticulum, where the substrate is oxidized by the H6PD to generate NADPH. As H6PD operates in conjunction with 11β-HSD1, the increased level of NADPH is utilized by the latter enzyme to convert inactive cortisone to active cortisol. Administration of cortisone to Mg2+ defi cient hepatocytes results in a marked production of cortisol, which in turn enhances gluconeogenesis and alters intrahepatic fatty acid synthesis, thus increasing intrahepatic triglyceride levels. Protein and mRNA expression of H6PD and 11β-HSD1 are both increased 3-4 fold in Mg2+ defi cient cells. Mg2+ defi cient hepatocytes also exhibit decreased insulin responsiveness, which is further compromised by cortisol production. Returning cellular Mg2+ content to its physiological levels, results in a dramatic decrease in cortisol production, and in the progressive renormalization of expression and activity of H6P, 11β-HSD1, and cortisol-responsive genes. Investigation into the underlying mechanism of action suggest that under Mg2+ defi cient conditions 11β-HSD1 expression and activity increase as a consequence of increased nuclear translocation of NF-kB and increased expression of infl ammatory cytokines (namely IL-1β and/or TNFα). Taken together, our results suggest that by increasing H6PD and 11β-HSD1 activity and expression, Mg2+ deficiency sets the conditions for an increased intrahepatic production of cortisol and decreased insulin responsiveness. Th is altered hormonal balance can play a major role in the onset and progression of the metabolic syndrome and its associated complications.