Earlier studies
have led to the model of "metabolic zonation" of liver parenchyma (e.g. glucose
uptake in the perivenous and glucose output in the periportal zone): The model
is based on the zonation of the enzyme equipment of the parenchymal cells
following the differential expression of the same genome. Further studies
have shown that gene expression of the glucagon-induced cytosolic
phosphoenolpyruvate carboxykinase 1 (PCK-1) is positively and that
of the insulin-induced glucokinase (GK) is negatively modulated by
oxygen. A CO-sensitive heme protein with oxidase activity which leads
to the production of H2O2 as intracellular second messenger, appeared
to be involved in the signalling cascade. H2O2 acted indirectly via the hydroxyl
radical that was formed from H2O2 at the endoplasmic reticulum via a Fe2+-catalyzed
Fenton reaction.
A normoxia response element in the PCK-1 promoter and a
a hypoxia response element binding the hypoxia-inducible factor-1 in the GK promoter
were identified (Fig. 1). The investigations will be continued with more detailed experiments on
the nature of the heme protein as well as the O2-responsive gene elements and
the O2-modulated transcription factors.
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