title: Inflammatory stress exacerbates hepatic cholesterol accumulation via disrupting cellular cholesterol export.
abstract: OBJECTIVE
  Both inflammation and cholesterol accumulation play important roles in the development of non-alcoholic fatty liver disease. This study was undertaken to investigate whether inflammation aggravated cholesterol accumulation via disrupting hepatic cholesterol export and we explored the underlying mechanisms.
  
  
  METHODS
  We used casein injection in C57BL/6J mice, and tumor necrosis factor alpha (TNF-α) stimulation in human hepatoblastoma cell line (HepG2) cells to induce inflammation. Intracellular cholesterol level was examined by Oil Red O staining and quantitative analysis. Bile acid level was quantified by colorimetric analysis. (3)[H] cholesterol assay by scintillation counting was performed to evaluate the cholesterol efflux. The mRNA and protein expression was examined by real-time polymerase chain reaction and Western blot.
  
  
  RESULTS
  Inflammation increased cholesterol accumulation in livers of C57BL/6J mice and in HepG2 cells. High-fat diet in mice and low-density lipoprotein (LDL) loading in HepG2 cells increased bile acid synthesis and cholesterol efflux, enhanced the mRNA and protein expression of liver X receptor α (LXRα), peroxisome proliferator-activated receptors (PPARα, γ), cholesterol 7α-hydroxylase (CYP7A1) and ATP-binding cassette transporter A1 (ABCA1). However, inflammation reduced bile acid synthesis and cholesterol efflux even in high-fat-diet-fed mice and HepG2 cells in the presence of LDL loading. The enhanced effects of these genes and proteins expression due to high-fat diet and LDL loading were inhibited by inflammation both in vivo and in vitro.
  
  
  CONCLUSIONS
  Inflammation disrupted PPAR-LXR-CYP7A1/ABCA1-mediated bile acid synthesis and cholesterol efflux resulting in exacerbated cholesterol accumulation in livers of C57BL/6J mice and HepG2 cells.
authors.affiliation: Chongqing Key Laboratory of Lipid and Glucose Metabolism, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Chen
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.forename: Mei
authors.initials: M
authors.lastname: Mei
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Ailong
authors.initials: A
authors.lastname: Huang
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002364:Caseins; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D056945:Hep G2 Cells; D006505:Hepatitis / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002364:Caseins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase