HIF‐1 is not a critical determinant for metabolic zonation in liver acinus

Abstract

In liver, hepatocytes show zonal expression of enzymes involved in carbohydrate metabolisms depending on their localizations in acinus. Among factors responsible for the metabolic zonation, oxygen has been thought to play a critical role for hepatocytes to express distinct enzymes by sensing changes in oxygen concentrations in liver acinus. This study aims to elucidate whether hypoxia inducible factor (HIF)‐1, an oxygen‐sensitive transcription factor, serves as a molecular determinant in the establishment of metabolic zonation of hepatocytes among liver acinus. To this end, we inactivated gene of HIF‐1α, a subunit of HIF‐1 that control its transcriptional activity, in a hepatocyte‐specific manner in mice. HIF‐1α (−/−) mice are viable without any apparent abnormalities of development. Immunohistochemical analysis revealed that expressions and distributions of carbohydrate‐related enzymes including glucokinase (GK) were comparable between control and HIF‐1α (−/−) mice. Exposure to 8 % hypoxia induced expressions of pyruvate kinase and GK greatly as a function of time in isolated control hepatocytes, while the induction was delayed and attenuated in HIF‐1α‐deficient hepatocytes. These results suggest that HIF‐1 is not essential for the maintenance of metabolic zonation in liver acinus, but is required for hypoxic responses of hepatocytes in enzyme expressions.