Modulation of the Glucagon-Dependent Induction of Phosphoenolpyruvate Carboxykinase and Tyrosine Aminotransferase by Arterial and Venous Oxygen Concentrations in Hepatocyte Cultures

Abstract

Periportal and perivenous hepatocytes are heterogeneous as to their outfit with enzymes and subcellular structures. The influence of different physiological oxygen concentrations on gene expression was studied in primary cultures of adult rat hepatocytes. 1 In 24-cultures the activities of phosphoenolpyruvate carboxykinase andtyrosine aminotransferase, which are predominantly located in periportal cells, were increased by glucagons(0.1 μmol/1)within 4 h to higher levels under 13%(v/v)oxygen in the gas atmosphere (mimicking arterial oxygen concentrations)than under 6%(v/v)oxygen (mimicking venous oxygen concentrations). The increase was due to enzyme induction as indicated by its prevention with cycloheximide or actinomycin D and by direct immunochemical titration. 2 Half-maximal induction of phosphoenolpyruvate carboxykinase and tyrosine aminotransferase was obtained under high and low oxygen tensions with glucagons concentrations around 0.5 nmol/1. 3 The induction of phosphoenolpyruvate carboxykinase and tyrosine aminotransferase by glucagons showed a sigmoidal rather than a linear dependence on oxygen tension; the range of highest sensitivity was found to be between 8% and 11% oxygen(v/v). 4 The oxygen dependence of the induction of phosphoenolpyruvate carboxykinase and tyrosine aminotransferase was probably specific and did not reflect a general impairment of energy metabolism. In the hapatocytes cultured under 13% and 6% oxygen (v/v) a)the adenine nucleotide levels were essentially the same the energy charge being 0.89;(b)the oxygen consumption was similar, 2.42±0.10 and 2.27±0.26μmol min −1wet weight −1; and (c)incorporation of [14] leucine into cellular protein as a measure of general protein synthesis amounted to 6.9 ±0.38 and 6.0 ± 0.4. nmol min −1mg DNA−1. The present results demonstrate that different physiological oxygen tensions can modulate the induction of liver enzymes and can thus contribute to the heterogeneity of hapatocytes.