title: Targeted expression of uncoupling protein 2 to mouse liver increases the susceptibility to lipopolysaccharide/galactosamine-induced acute liver injury.
abstract: Normal hepatocytes do not express endogenous uncoupling protein 2 (UCP2) in adult liver, although Kupffer cells do, and it is strikingly induced in hepatocytes in steatotic liver and obese conditions. However, the direct link of UCP2 with the pathogenic development of liver diseases and liver injury remains elusive. Here we report that targeted expression of UCP2 to mouse liver increases susceptibility to acute liver injury induced by lipopolysaccharide (LPS) and galactosamine (GalN). UCP2 appears to enhance proton leak, leading to mild uncoupling in a guanosine diphosphate-repressible manner. Indeed, mitochondria from the genetically manipulated mouse liver have increased state 4 respiration, lower respiratory control ratio, and reduced adenosine triphosphate (ATP) levels, which altered mitochondrial physiology. To address the underlying mechanism of how UCP2 and the reduced energy coupling efficiency enhance cell death in mouse liver, we show that the reduced ATP levels lead to activation of 5'AMP-activated protein kinase (AMPK) and its downstream effector, c-Jun N-terminal kinase; thus, the increased sensitivity toward LPS/GalN-induces apoptosis. Importantly, we show that inhibition of UCP2 activity by its pharmacological inhibitor genipin prevents LPS/GalN-induced ATP reduction, AMPK activation, and apoptosis. Also, inhibition of ATP production by oligomycin promotes LPS/GalN-induced cell death both in vivo and in vitro.
  
  
  CONCLUSIONS
  Our results clearly show that targeted expression of UCP2 in liver may result in compromised mitochondrial physiology that contributes to enhanced cell death and suggests a potential role of UCP2 in the development of liver diseases.
authors.affiliation: Laboratory of Apoptosis and Cancer Biology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Shang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Du
authors.forename: Youliang
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Cheng
authors.forename: Weiming
authors.initials: W
authors.lastname: Xiao
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Haijing
authors.initials: H
authors.lastname: Jin
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Shusen
authors.initials: S
authors.lastname: Liu
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005688:Galactosamine / Q000009:adverse effects*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D005688:Galactosamine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D055372:AMP-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3