Atorvastatin protects obese mice against hepatic ischemia–reperfusion injury by Toll‐like receptor‐4 suppression and endothelial nitric oxide synthase activation

Abstract

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.

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

“…Moreover, the observed increase in NO may be an adaptive response of the injured liver. Ajamieh et al (2012) found that there were increases in NOS3 levels and NOS3 phosphorylations after liver injury in NASH, and they were found to be protective against NASH. Based on these observations, we argued that though NO is considered proinflammatory and an M1 marker, the kinetics of NO release and its concentration in the hepatic microenvironment might play an adaptive and perhaps a protective role in the pathophysiology of NASH.…”

“…NO, released from any of the three NOS upon their activation, plays a significant role in inflammation (Fujita et al, 2010;Ajamieh et al, 2012). However, the inducible form of the NOS has been ascribed to the proinflammatory phenotype more often (Fujita et al, 2010;Maina et al, 2012).…”

“…Ajamieh et al (2012) reported that atorvastatin conferred 70%-90% hepatic protection in NASH. The increased expression of Toll-like receptor-4 and activation of nuclear factor-kB were abrogated by the administration of atorvastatin, which was found to activate endothelial NOS (eNOS/NOS3) (Ajamieh et al, 2012). Prevention and reversion of nonalcoholic steatohepatitis in ob/ob mice by S-nitroso-N-acetylcysteine treatment has been reported in leptin deficient mice (ob/ob), but there was no mechanistic insight about the protection seen (de Oliveira et al, 2008).…”

“…They hypothesized, based on the published studies, that increased NO may be contributing to excess nitrotyrosine, and hence, increasing oxidativenitrosative stress in the liver (Fujita et al, 2010). Ajamieh et al (2012) reported that atorvastatin conferred 70%-90% hepatic protection in NASH. The increased expression of Toll-like receptor-4 and activation of nuclear factor-kB were abrogated by the administration of atorvastatin, which was found to activate endothelial NOS (eNOS/NOS3) (Ajamieh et al, 2012).…”

Enhancing organ pool by statins: Is this the future?

“…9 The study from Ajamieh and colleagues published this month in the Journal of Gastroenterology and Hepatology provides new and important concepts regarding the use of statins as prophylactic agents to prevent warm I/R injury in the liver. 10 This study, conducted in experimental models of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), demonstrated that oral administration of atorvastatin for 10 days prior to warm I/R injury markedly prevented hepatocellular damage. Although readers might now think that the herein published study represents a reiteration of the Llacuna study, it is not.…”