Abstract
Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.
Highlights
Acute pancreatitis (AP) is a highly fatal acute inflammation with rapid progression. (Argaiz and de Moraes, 2021)
We investigated whether the direct adenosine monophosphate protein kinase (AMPK) activator Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (400 mg/kg) alleviates pancreatitis-associated liver injury by AMPK activation in a rat model of sodium taurocholate-induced severe acute pancreatitis (SAP)
The above results suggest that sodium taurocholate infusion established a successful rat model of pancreatitis-associated liver injury (PALI) and that supplementation with AICAR reduces the severity of pancreatitis and attenuates PALI and restores liver function in sodium taurocholate-induced SAP rats
Summary
Acute pancreatitis (AP) is a highly fatal acute inflammation with rapid progression. (Argaiz and de Moraes, 2021). The high mortality of AP is largely attributed to multiple organ dysfunction syndrome (MODS), such as liver or lung injury (Shi et al, 2020). Pancreatitis-associated liver injury (PALI) is a serious and even fatal complication in the development of AP (Wang et al, 2018). A series of endogenous vasoactive substances released during AP lead to hepatic microcirculation disturbance, which is the essential cause of liver injury (Wenhong et al, 2012). The PALI phenomenon has been observed in both clinical and experimental settings (Wang et al, 2006; Wenhong et al, 2012; Lv et al, 2015; Bakır et al, 2016; Ou et al, 2017). Finding a promising therapeutic way to prevent or treat this devastating and fatal disease is urgently needed
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