title: Activation of liver X receptors attenuates endotoxin-induced liver injury in mice with nonalcoholic fatty liver disease.
abstract: OBJECTIVE
  Nonalcoholic fatty liver disease (NAFLD) is classically associated with insulin resistance and the inflammatory response, especially in the nonalcoholic steatohepatitis phase. The liver X receptors (LXRs) play a critical role in the regulation of cholesterol metabolism and inflammatory processes.
  
  
  METHODS
  Wild-type C57BL/6 mice were fed a normal diet (ND) or a high-fat (HF) diet for 8 weeks. Some ND- and HF-fed mice were treated (i.p.) with the LXR agonist T0901317 (30 mg/kg/day) for 7 days. Lipopolysaccharide (LPS, 50 μg/mouse) was then injected intraperitoneally to induce liver injury. The activation of MAPKs, NF-κB and the PI3K pathway was evaluated using Western blot. Bone marrow-derived macrophages (MDMs) were isolated from the femurs of C57BL/6 mice and cultured with or without T0901317 (20 μmol/l). The expression of tumor necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) was evaluated in vitro or in vivo using real-time PCR, immunohistochemistry, or Western blot.
  
  
  RESULTS
  The LXR agonist T0901317 attenuated LPS-induced liver injury in a murine model of NAFLD, reflected by reduced serum alanine aminotransferase and aspartate aminotransferase levels, and reduced liver histology changes. Activation of LXRs reduced TNF-α and iNOS expression through inhibiting JNK and the PI3K signaling pathway. An in vitro study demonstrated that the activation of LXR inhibited the expression of TNF-α and iNOS in the MDMs of mice.
  
  
  CONCLUSIONS
  Activation of LXRs attenuates LPS-induced liver injury in murine NAFLD through inhibiting the pro-inflammatory activity of macrophages.
authors.affiliation: Department of Gastroenterology, Shanghai Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine, 145 Shandong Middle Road, Shanghai, 200001, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.forename: Zhaolian
authors.initials: Z
authors.lastname: Bian
authors.forename: Yanshen
authors.initials: Y
authors.lastname: Peng
authors.forename: Zhengrui
authors.initials: Z
authors.lastname: You
authors.forename: Qixia
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chen
authors.forename: Dekai
authors.initials: D
authors.lastname: Qiu
authors.forename: Xiong
authors.initials: X
authors.lastname: Ma
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007150:Immunohistochemistry; D050155:Lipogenesis / Q000502:physiology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D006845:Hydrocarbons, Fluorinated; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides