title: Hypoxia induces dysregulation of lipid metabolism in HepG2 cells via activation of HIF-2α.
abstract: BACKGROUND
  Hypoxia is a risk factor for non-alcoholic fatty liver diseases, leading to permanent imbalance of liver lipid homeostasis and steatohepatitis. The current study examined the effect of HIF-2α, an oxygen-sensitive heterodimeric transcription factor, on hypoxia-induced dysregulation of lipid metabolism in HepG2 cells.
  
  
  METHODS
  Studies were conducted in C57BL/6 male mice and human HepG2 cells under hypoxic conditions, transfected with HIF-2α-targeted shRNA. The mRNA and protein expressions of key genes relevant to lipid metabolism were determined via RT-qPCR and western blot, respectively. Intracellular lipid accumulation was determined by Nile red, filipin staining and quantitative assay kits.
  
  
  RESULTS
  HIF-2α protein was quantified in both HepG2 cells and C57BL/6 mice under hypoxic conditions. Intracellular lipid accumulation and increased lipid levels induced by hypoxia were significantly reduced by silence of HIF-2α expression, associated with reversed expression of ABCA1 and ADRP, key genes in involved cholesterol excretion and fatty acid uptake respectively. However, HIF-2α had no effect on enzymatic activity and expression of key genes involved in fatty acid β-oxidation or cholesterol metabolism.
  
  
  CONCLUSIONS
  Inhibition of HIF-2α protein reversed lipid metabolism dysregulation induced by acute hypoxia in HepG2 cells, which suggested that HIF-2α signaling may be relevant to oxygen-dependent lipid homeostasis in the liver.
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Risheng
authors.initials: R
authors.lastname: Cao
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Zhao
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.forename: Haiyun
authors.initials: H
authors.lastname: Zhou
authors.forename: Weixu
authors.initials: W
authors.lastname: Chen
authors.forename: Lihua
authors.initials: L
authors.lastname: Ren
authors.forename: Xiqiao
authors.initials: X
authors.lastname: Zhou
authors.forename: Hongjie
authors.initials: H
authors.lastname: Zhang
authors.forename: Ruihua
authors.initials: R
authors.lastname: Shi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D010100:Oxygen; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1