Hypoxia-Inducible Factor-1 Is a Determinant of Lobular Structure and Oxygen Consumption in the Liver

Objective Hypoxia-inducible factor is a hypoxia-responsive transcriptional factor that controls the expression of proteins contributing to homeostatic responses to hypoxia. Spatial heterogeneity of tissue oxygenation has been postulated as a determinant of structure and function of hepatic lobules, although its molecular mechanisms remain unknown. This study aimed to examine the role of HIF-1 expressed in hepatocytes in regulation of hepatic microcirculation. Methods We have generated mice harboring a floxed HIF-1 alpha allele, and employed the albumin-Cre transgenic line to inactivate the gene site-specifically in hepatocytes. Results Intravital observation of the hepatic microcirculation revealed extension of hepatic lobules in HIF-1 alpha-deficient mice. Measurement of microvascular diameter, velocity, and local oxygen tension by laser-assisted phosphorimetry showed that the oxygen consumption in the lobules of HIF-1 alpha-deficient mice was greater than that in those of control mice. Isolated hepatocytes from HIF-1 alpha-deficient mice also stimulated oxygen consumptions with increased contents of mtDNA. Overexpression of HIF-1 alpha decreased the expression of PGC-1 alpha mRNA, whereas the knockdown of the HIF-1 alpha gene increased it, suggesting that HIF-1 regulates cellular respiration through mitochondrial biogenesis. Conclusions Our results suggest that constitutive expression of HIF-1 alpha in hepatocytes acts as a determinant of hepatic lobular structure and oxygen consumption by changing mitochondrial contents.