AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation

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.

Co-Treatment With Resveratrol and FGF1 Protects Against Acute Liver Toxicity After Doxorubicin Treatment via the AMPK/NRF2 Pathway

“…Activation of AMPK/NRF2 signaling molecules was also shown to protect against DOX-induced cardiomyopathy and acetaminophen-induced acute liver failure ( Lv et al, 2019 ; Wu et al, 2020 ). NRF2 is controlled by AMPK, which further boosts the transcription initiation of downstream antioxidant genes of NRF2 ( Qu et al, 2016 ; Wang et al, 2019b ; Ding et al, 2020 ; Kong et al, 2021 ). Moreover, activation of the AMPKα and NRF2 pathways was shown to effectively protect the liver from cellular oxidative stress ( Lee et al, 2020 ).…”

Bio-Waste Products of Mangifera indica L. Reduce Adipogenesis and Exert Antioxidant Effects on 3T3-L1 Cells

“…Notably, Nrf2 and AMPK has been shown to be functionally connected and collaborate to reduce oxidative stress. Induction of AMPK by natural compounds [ 73 ] or chemical activators [ 74 ] leads in turn to activation via phosphorylation of Nrf2. This has been correlated with a reduction in inflammation in several cell types, as adipocytes, macrophages and pancreatic cells [ 74 , 75 ].…”

“…Induction of AMPK by natural compounds [ 73 ] or chemical activators [ 74 ] leads in turn to activation via phosphorylation of Nrf2. This has been correlated with a reduction in inflammation in several cell types, as adipocytes, macrophages and pancreatic cells [ 74 , 75 ]. Thus, MPE and MSE could explain antioxidant effects by promoting activation of both AMPK and Nrf2 in 3T3-L1 adipocytes.…”

Putative molecular targets for vitamin A in neutralizing oxidative stress in acute and chronic pancreatitis — a systematic review

“…Our review revealed that TLR signaling may be crucial in the antioxidative defense, as well as AMP and MAPK pathways; thus, these factors might become potential therapeutic targets in treatment of AP and/or CP. Moreover, the authors mentioned that several different factors, such as NLRP3, PI3K/AKT/mTOR, or NFκB, are involved in the pathogenesis of AP and/or CP, though a detailed correlation between them and OS was not evaluated (Xue, et al 2019;Kong et al 2021;Tarasiuk et al 2021). Moreover, given that the factors mentioned above are involved in regulating cellular death, further studies examining the impact of OS on their expression and its influence on cellular death would by highly interesting.…”

“…Given that current literature describes VA as an antiproliferative, anti-inflammatory, and antioxidative agent, it seems that VA should alleviate symptoms of AP and CP; however, some conflicting results were reported. To fully elucidate the impact of VA on OS in AP and CP, further studies with well-designed Liu et al 2018;Li et al 2018;Namachivayam et al 2015;Pan et al 2017;Pan et al 2016;Hong 2020;Xie et al 2021;Li et al 2017;Sierra-Mondragon et al 2018;Kim et al 2013;Cheng et al 2021;Huang et al 2019;Bernardo et al 2013;Szabo et al 2012;Ren and Shen 2019;Bansod et al 2020;Tarasiuk et al 2019;Kim et al 2015;Ishijima et al 2015;Yun et al 2008;Gao, et al 2021;Xue, et al 2019;Kong et…”