title: Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice.
abstract: OBJECTIVE
  Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice.
  
  
  METHODS
  Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR.
  
  
  RESULTS
  A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-κB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice.
  
  
  CONCLUSIONS
  These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis.
authors.affiliation: Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Ruby L C
authors.initials: RL
authors.lastname: Hoo
authors.forename: Ida P C
authors.initials: IP
authors.lastname: Lee
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.forename: Janice Y L
authors.initials: JY
authors.lastname: Wong
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hui
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D001713:Biphenyl Compounds; D002791:Cholesterol, Dietary; D016207:Cytokines; D004041:Dietary Fats; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D011720:Pyrazoles