Hypoxia-inducible factor-1 is a determinant of lobular structure and oxygen consumption in the liver

Kosuke Tsukada, Toshihide Tajima, Shutaro Hori, Tomomi Matsuura, Randall S. Johnson, Nobuhito Goda, Makoto Suematsu

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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-1α 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-1α-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-1α-deficient mice was greater than that in those of control mice. Isolated hepatocytes from HIF-1α-deficient mice also stimulated oxygen consumptions with increased contents of mtDNA. Overexpression of HIF-1α decreased the expression of PGC-1α mRNA, whereas the knockdown of the HIF-1α gene increased it, suggesting that HIF-1 regulates cellular respiration through mitochondrial biogenesis. Conclusions: Our results suggest that constitutive expression of HIF-1α in hepatocytes acts as a determinant of hepatic lobular structure and oxygen consumption by changing mitochondrial contents.

Original languageEnglish
Pages (from-to)385-393
Number of pages9
JournalMicrocirculation
Volume20
Issue number5
DOIs
Publication statusPublished - 2013 Jul 1
Externally publishedYes

Keywords

  • HIF-1α
  • Liver
  • Mitochondrial biogenesis
  • Oxygen consumption

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Hypoxia-inducible factor-1 is a determinant of lobular structure and oxygen consumption in the liver'. Together they form a unique fingerprint.

  • Cite this

    Tsukada, K., Tajima, T., Hori, S., Matsuura, T., Johnson, R. S., Goda, N., & Suematsu, M. (2013). Hypoxia-inducible factor-1 is a determinant of lobular structure and oxygen consumption in the liver. Microcirculation, 20(5), 385-393. https://doi.org/10.1111/micc.12033