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Cross-Talk between the Signals Hypoxia and Glucose at the Glucose Response Element of the L-Type Pyruvate Kinase Gene¹

Institut für Biochemie und Molekulare Zellbiologie, Georg-August-Universität, Humboldtallee 23, D-37073 Göttingen, Germany

Address all correspondence and requests for reprints to: Thomas Kietzmann, M.D., Institut für Biochemie und Molekulare Zellbiologie, Humboldtallee 23, D-37073 Göttingen, Germany.

The signals oxygen and glucose play an important role in metabolism, angiogenesis, tumorigenesis, and embryonic development. Little is known about an interaction of these two signals. We demonstrate here the cross-talk between oxygen and glucose in the regulation of L-type pyruvate kinase (L-PK) gene expression in the liver. In the liver the periportal to perivenous drop in O₂ 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 pO₂, whereas its glucose-dependent induction occurred predominantly under arterial pO₂. It was shown by transient transfection of L-PK promoter luciferase and glucose response element (Glc_PKRE) SV40 promoter luciferase gene constructs that the modulation by O₂ of the glucose-dependent induction occurred at the Glc_PKRE in the L-PK gene promoter. The reduction of the glucose-dependent induction of the L-PK gene expression under venous pO₂ appeared to be mediated via an interference between hypoxia inducible factor-1 (HIF-1) and upstream stimulating factor at the Glc_PKRE. The glucose response element also functioned as an hypoxia response element which was confirmed in cotransfection assays with Glc_PKRE luciferase gene constructs and HIF-1 expression vectors. Furthermore, it was found by gel shift and supershift assay that HIF-1 and USF-1 or USF-2 could bind to the Glc_PKRE. Our findings implicate that the cross-talk between oxygen and glucose might have a fundamental role in the regulation of several physiological and pathophysiological processes.

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