Rebuilding of Carbohydrate and Lipid Metabolism Under Hypoxia: Regularities and Therapeutic Possibilities

Abstract

Previously, we have found that the effects of chronic (staying in midlands) or moderate periodic hypoxia as well as hypoxic preconditioning is accompanied by beneficial refbuilding in lipid and carbohydrate metabolism in human and animals: a reduction of total cholesterol and its fractions in blood plasma, a hypoglycemic reaction or normalization of elevated blood glucose, and a decrease of impaired glucose tolerance. This metabolic rebuilding has a phase character during the adaptation to hypoxia and following deadaptation. Changes in metabolism during hypoxia occur in a consecutive manner and mediate by induction and repression of target genes following activation of hypoxia responsible signal ways and transcription factors. In particular, we showed the alternate transactivation of HIF-1alpha and -3alpha subunits, and the restructuring of glucose transport by consecutive induction of GLUT-4 and -1 in rat myocardium and lungs. Mitochondrial respiration is consequentially shifted from down - to up- regulation, and from carbohydrate to mainly lipid substrate using. In human, we found attenuation of transcriptional regulator of cholesterol synthesis SREBP-1, leptin and insulin-like growth factor IGF-1 levels in blood plasma under prolonged hypoxic conditions, as well as positive correlation with HIF-dependent protein IGF-1 and HDL-cholesterol level. In middle-aged people with metabolic disorders (metabolic syndrome, diabetes mellitus, dyslipidemia), favorable influence of staying in midlands, moderate acute or periodic hypoxia was found, but metabolic pathology was associated with altered pattern of regulatory protein expression. The data suggest the close relationship between carbohydrate and lipid metabolism under hypoxia, and evidence the possibility of hypoxic correction of metabolic disorders as diabetes, dyslipidemia and metabolic syndrome based on phase processes of metabolic rebuilding.