title: Hypoxia-inducible factor-1 is a determinant of lobular structure and oxygen consumption in the liver.
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.
authors.affiliation: Department of Applied Physics and Physico-Informatics, Faculty of Science and Technology, Keio University, Kouhoku-ku, Yokohama, Japan. ktsukada@appi.keio.ac.jp
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tsukada
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tajima
authors.forename: Shutaro
authors.initials: S
authors.lastname: Hori
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Goda
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors