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Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation.
J Gastroenterol Hepatol. 2012 Aug; 27(8):1353-61.JG

Abstract

BACKGROUND AND AIM

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.

CONCLUSION

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+Show Affiliations

Gastroenterology and Hepatology Unit, Australian National University Medical School, the Canberra Hospital, Australian Capital Territory, Canberra, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22432744

Citation

Ajamieh, Hussam, et al. "Atorvastatin Protects Obese Mice Against Hepatic Ischemia-reperfusion Injury By Toll-like Receptor-4 Suppression and Endothelial Nitric Oxide Synthase Activation." Journal of Gastroenterology and Hepatology, vol. 27, no. 8, 2012, pp. 1353-61.
Ajamieh H, Farrell G, Wong HJ, et al. Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. J Gastroenterol Hepatol. 2012;27(8):1353-61.
Ajamieh, H., Farrell, G., Wong, H. J., Yu, J., Chu, E., Chen, J., & Teoh, N. (2012). Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. Journal of Gastroenterology and Hepatology, 27(8), 1353-61. https://doi.org/10.1111/j.1440-1746.2012.07123.x
Ajamieh H, et al. Atorvastatin Protects Obese Mice Against Hepatic Ischemia-reperfusion Injury By Toll-like Receptor-4 Suppression and Endothelial Nitric Oxide Synthase Activation. J Gastroenterol Hepatol. 2012;27(8):1353-61. PubMed PMID: 22432744.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. AU - Ajamieh,Hussam, AU - Farrell,Geoffrey, AU - Wong,Heng Jian, AU - Yu,Jun, AU - Chu,Eagle, AU - Chen,Jeffrey, AU - Teoh,Narci, PY - 2012/3/22/entrez PY - 2012/3/22/pubmed PY - 2012/12/27/medline SP - 1353 EP - 61 JF - Journal of gastroenterology and hepatology JO - J Gastroenterol Hepatol VL - 27 IS - 8 N2 - BACKGROUND AND AIM: 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. CONCLUSION: 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. SN - 1440-1746 UR - https://www.unboundmedicine.com/medline/citation/22432744/Atorvastatin_protects_obese_mice_against_hepatic_ischemia_reperfusion_injury_by_Toll_like_receptor_4_suppression_and_endothelial_nitric_oxide_synthase_activation_ L2 - https://doi.org/10.1111/j.1440-1746.2012.07123.x DB - PRIME DP - Unbound Medicine ER -