title: Positive cross-talk between hypoxia inducible factor-1α and liver X receptor α induces formation of triglyceride-loaded foam cells.
abstract: OBJECTIVE
  Atherosclerosis is a chronic and progressive inflammatory disease of the arteries that is characterized by subendothelial accumulation of lipid-rich macrophages, called foam cells. We sought to identify the molecular details of cross-talk between liver X receptor α (LXRα) and hypoxia-inducible factor 1α (HIF-1α) for the formation of triglyceride-rich foam cells under hypoxic conditions.
  
  
  RESULTS
  We first observed that expression of LXRα and its target lipogenic genes was time-dependently induced in human primary macrophages and RAW 264.7 cells under hypoxia. Similarly, TO901317, an activator of LXRα, enhanced the expression level and the transcriptional activity of HIF-1α. Second, we demonstrated that LXRα increased HIF-1α protein stability through a physical interaction between the ligand binding domain of LXRα and the oxygen-dependent degradation domain of HIF-1α. Third, we found that the activation of HIF-1α or LXRα synergistically induced triglyceride accumulation in macrophages. Finally, we showed that LXRα and HIF-1α were codistributed in the macrophages of atherosclerotic lesions of patients.
  
  
  CONCLUSIONS
  These results suggest that the positive feed-forward regulation of transcriptional activity and protein stability of LXRα and HIF-1α has an important impact in foam cell formation.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Na
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyeon-Jeong
authors.initials: HJ
authors.lastname: Oh
authors.forename: Seung
authors.initials: S
authors.lastname: Huh
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D023421:Models, Animal; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D020239:Receptor Cross-Talk / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D014280:Triglycerides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides