Cross-talk between the signals hypoxia and glucose at the glucose responseelement of the L-type pyruvate kinase gene

The signals oxygen and glucose play an important role in metabolism, angiog enesis, tumorigenesis, and embryonic development. Little is known about an interaction of these two signals. We demonstrate here the cross-talk betwee n oxygen and glucose in the regulation of L-type pyruvate kinase (L-PK) gen e expression in the liver. In the liver the periportal to perivenous drop i n O-2 tension was proposed to be an endocrine key regulator for the zonated gene expression. In primary rat hepatocyte cultures the expression of the L-PK gene on mRNA and on protein level was induced by venous pO(2), whereas its glucose-dependent induction occurred predominantly under arterial pO(2 ). It was shown by transient transfection of L-PK promoter luciferase and g lucose response element (Glc(PK)RE) SV40 promoter luciferase gene construct s that the modulation by O-2 of the glucose-dependent induction occurred at the Glc(PK)RE in the L-PK gene promoter. The reduction of the glucose-depe ndent induction of the L-PK gene expression under venous pO(2) appeared to be mediated via an interference between hypoxia inducible factor-1 (HIF-1) and upstream stimulating factor at the Glc(PK)RE. The glucose response elem ent also functioned as an hypoxia response element which was confirmed in c otransfection assays with Glc(PK)RE luciferase gene constructs and HIF-1 al pha expression vectors. Furthermore, it was found by gel shift and supershi ft assay that HIF-1 alpha and USF-1 or USF-2 could bind to the Glc(PK)RE. O ur findings implicate that the cross-talk between oxygen and glucose might have a fundamental role in the regulation of several physiological and path ophysiological processes.