title: Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation.
abstract: OBJECTIVE
  Steatosis accentuates the severity of hepatic ischemia-reperfusion injury (IRI). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") protect the heart and brain against post-ischemic injury, without necessarily lowering serum cholesterol. We tested whether 10-day or 1-day atorvastatin administration protects livers with fatty change or non-alcoholic steatohepatitis (NASH) against IRI.
  
  
  METHODS
  Mice with dietary or genetic simple steatosis (SS) or NASH were subjected to 60 min of partial hepatic ischemia/24-h reperfusion, with/without atorvastatin administered with food (5 mg/kg body weight) for 10 days, or injected intravenously (5 mg/kg) 24 h before ischemia. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, endothelial nitric oxide synthase (eNOS), activation and thromboxane B2 production were determined.
  
  
  RESULTS
  Atorvastatin conferred 70-90% hepatic protection against IRI in obese animals with SS or NASH, in which IRI was accentuated twofold to fivefold. IRI markedly upregulated TLR4 and activated nuclear factor-κB (NF-κB); atorvastatin abrogated these effects, as well as activating eNOS. Atorvastatin dampened the post-ischemic induction of thromboxane B2, macrophage inflammatory protein-1a, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin (IL)-12 p40, γ-interferon, IL-6, and adhesion molecules (vascular cell adhesion molecule-1, E-selectin, vascular endothelial-cadherin), and reduced macrophage and neutrophil recruitment. There was no reduction in serum cholesterol that could explain these effects, and hepatic cholesterol was normal in these mice. A single 24-h injection of atorvastatin conferred equivalent hepatoprotection.
  
  
  CONCLUSIONS
  Statins exert major hepatoprotection against IRI in lean, fatty, and NASH livers that is not due to cholesterol removal. Rather, statins downregulate TLR4 to prevent NF-κB activation, with resultant suppression of adhesion molecules, chemokines/cytokines, and thromboxane B2 production. Short-term statin treatment is an effective, readily-available preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease.
authors.affiliation: Gastroenterology and Hepatology Unit, Australian National University Medical School, the Canberra Hospital, Australian Capital Territory, Canberra, Australia.
authors.forename: Hussam
authors.initials: H
authors.lastname: Ajamieh
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Farrell
authors.forename: Heng Jian
authors.initials: HJ
authors.lastname: Wong
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Eagle
authors.initials: E
authors.lastname: Chu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chen
authors.forename: Narci
authors.initials: N
authors.lastname: Teoh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004789:Enzyme Activation; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000276:immunology; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011758:Pyrroles; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013929:Thromboxane B2; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse