title: Role of Kupffer cells in ischemic injury in alcoholic fatty liver.
abstract: BACKGROUND
  This study was designed to evaluate the role of Kupffer cells (KCs) in hepatic drug metabolizing dysfunction after hepatic ischemia-reperfusion (IR) in alcoholic fatty liver.
  
  
  METHODS
  Rats were fed the Lieber-DeCarli diet for 5 wk to develop alcoholic fatty liver, then were subjected to 90 min of hepatic ischemia and 5 h of reperfusion. For ablation of KCs, rats were pretreated with gadolinium chloride (GdCl3) 48 and 24 h before the IR procedure.
  
  
  RESULTS
  After the IR procedure, ethanol diet (ED)-fed rats had higher serum aminotransferase activity compared with the control diet-fed rats. These changes were attenuated by GdCl3. The ED-fed rats exhibited increased hepatic microsomal total cytochrome P450 (CYP) content and nicotinamide adenine dinucleotide phosphate-CYP reductase and CYP1A1, 1A2, 2B1, and 2E1 isozyme activity. After hepatic IR, these increases were reduced to lower levels than observed in the sham group, except CYP2E1 activity. Increases in CYP2E1 activity and its expression were augmented after hepatic IR in ED-fed animals, but were attenuated by GdCl3. Finally, toll-like receptor 4 and myeloid differentiation primary response gene 88 protein expression, nuclear translocation of nuclear factor-κB and activator protein 1, and levels of proinflammatory mediators were further increased in ED-fed animals compared with control diet-fed animals after IR. These increases were attenuated by GdCl3.
  
  
  CONCLUSIONS
  We suggest that KCs contribute to hepatic drug metabolizing dysfunction during hepatic IR in alcoholic fatty liver via the toll-like receptors 4-mediated inflammatory response.
authors.affiliation: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Kang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea. Electronic address: sunmee@skku.edu.
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D059865:Endoplasmic Reticulum Stress; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D019392:Cytochrome P-450 CYP2E1
keywords: Alcoholic fatty liver; Cytochrome P450 isozymes; Hepatic ischemia–reperfusion; Kupffer cells; Reactive oxygen species; Toll-like receptor 4