title: Acute atorvastatin is hepatoprotective against ischaemia-reperfusion injury in mice by modulating eNOS and microparticle formation.
abstract: OBJECTIVE
  Steatosis accentuates the severity of hepatic ischaemia-reperfusion injury (IRI); 'statins' (HMG-CoA reductase inhibitors) protect the heart and brain against post-ischaemic injury. We tested whether short-term administration of atorvastatin protects fatty livers in obese mice against IRI.
  
  
  METHODS
  Mice with dietary or genetic simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) were subjected to 60 min partial hepatic ischaemia/24 h reperfusion. Atorvastatin was injected intravenously (5 mg/kg) 1 h before IRI. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, iNOS/eNOS expression, eNOS activity and thromboxane B2 (TXB2) production were determined.
  
  
  RESULTS
  Ischaemia-reperfusion injury was exaggerated by two- to five-fold in SS and NASH compared with lean liver. Atorvastatin pretreatment conferred 70-90% hepatic protection in all animals. Atorvastatin increased post-ischaemic eNOS mRNA/protein and strikingly enhanced eNOS activity (by phospho-eNOS). It also attenuated microparticle (MP) production, NF-κB activation, significantly dampened post-ischaemic thromboxane B2 production, induction of TNF-α, IL-6, MIP-1a, MCP-1, GM-CSF and vascular cell adhesion molecule-1 (VCAM), with a resultant reduction on macrophage and polymorphonuclear neutrophil recruitment. Up-regulation of HMGB1 and TLR4 after IRI was marked in fatty livers; 1 h pretreatment with atorvastatin reduced HMGB1 and TLR4 expression in all livers.
  
  
  CONCLUSIONS
  Acute (1 h) atorvastatin administration is highly hepatoprotective against IRI in NASH, fatty and lean livers. Key mechanisms include suppression of inflammation by prevention of NF-κB activation, microvascular protection via eNOS activation and suppression of TXB2 and MP release. Short-term intravenous statin treatment is a readily available and effective preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease, and merits clinical trials in at-risk patients.
authors: Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Garran, ACT, Australia.
authors: Hussam
authors: H
authors: Ajamieh
authors: Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Garran, ACT, Australia.
authors: Geoffrey C
authors: GC
authors: Farrell
authors: Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors: Robert S
authors: RS
authors: McCuskey
authors: Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong, China.
authors: Jun
authors: J
authors: Yu
authors: Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong, China.
authors: Eagle
authors: E
authors: Chu
authors: Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Garran, ACT, Australia.
authors: Heng-Jian
authors: HJ
authors: Wong
authors: Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Garran, ACT, Australia.
authors: Wesley
authors: W
authors: Lam
authors: Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Garran, ACT, Australia.
authors: Narci C
authors: NC
authors: Teoh
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000008:administration & dosage*; D018925:Chemokines / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D024243:HMGB1 Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008099:Liver / Q000473:pathology; 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 / Q000188:drug therapy*; D015427:Reperfusion Injury / Q000188:drug therapy*; D013929:Thromboxane B2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D013929:Thromboxane B2; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: atorvastatin; cytokines; microvascular protection; non-alcoholic fatty liver disease; toll-like receptor-4