In:
Liver International, Wiley, Vol. 35, No. 9 ( 2015-09), p. 2174-2186
Abstract:
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 ( TLR 4), cytokines/chemokines, iNOS / eNOS expression, eNOS activity and thromboxane B2 ( TXB 2) 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 HMGB 1 and TLR 4 after IRI was marked in fatty livers; 1 h pretreatment with atorvastatin reduced HMGB 1 and TLR 4 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 TXB 2 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.
Type of Medium:
Online Resource
ISSN:
1478-3223
,
1478-3231
DOI:
10.1111/liv.2015.35.issue-9
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2102783-3
detail.hit.zdb_id:
2124684-1
