title: UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway.
abstract: OBJECTIVE
  Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation.
  
  
  METHODS
  Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE－/－ mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages.
  
  
  RESULTS
  UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor α (LXRα) activation, which was confirmed by the observation that LXRα siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition.
  
  
  CONCLUSIONS
  Taken together, our results showed that UFM1 could suppress foam cell formation via the LXRα-dependent pathway.
authors.affiliation: Department of Endocrinology, Shanghai 3rd People's Hospital, School of Medicine, Shanghai Jiao Tong University.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Hu
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: He
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liu
authors.forename: Guang-Ya
authors.initials: GY
authors.lastname: Zhang
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Chen
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005487:Foam Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011506:Proteins; D012333:RNA, Messenger; C513664:Ufm1 protein, mouse; C099252:oxidized low density lipoprotein; D002784:Cholesterol