DUSP12 acts as a novel endogenous protective signal against hepatic ischemia–reperfusion damage by inhibiting ASK1 pathway

Abstract

Ischemia–reperfusion injury (IRI) consequent to major liver surgery is a still unmet clinical problem. The activation of endogenous systems of hepatoprotection can prevent the damaging effects of ischemia–reperfusion (IR) as shown by the phenomenon known as ‘ischemic preconditioning’. The identification of endogenous signal mediators of hepatoprotection is of main interest since they could be targeted in future therapeutic interventions. Qiu et al. recently reported in Clin. Sci. (Lond.) (2020) 134(17), 2279–2294, the discovery of a novel protective molecule against hepatic IR damage: dual-specificity phosphatase 12 (DUSP12). IR significantly decreased DUSP12 expression in liver whereas DUSP12 overexpression in hepatocytes protected IRI and DUSP12 deletion in DUSP12 KO mice exacerbated IRI. The protective effects of DUSP12 depended on apoptosis signal-regulating kinase 1 (ASK1) and acted through the inhibition of the ASK1-dependent kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These results enlighten DUSP12 as a novel intermediate negative regulator of the pro-inflammatory and pro-apoptotic ASK1/JNK-p38 MAPK pathway activated during hepatic IR and identify DUSP12 as potential therapeutic target for IRI.

Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation

“…We found that the stimulation of ASK1, that is induced at the time of reoxygenation by ER stress, is increased by hepatocellular steatosis through an ROS-dependent mechanism, and we showed that such increased ASK1 activation promoted liver inflammation and exacerbated JNK-dependent hepatocyte damage [10]. These findings indicate that pharmacologic interventions targeting ASK1 stimulation are a promising approach to protect against surgically induced IRI in humans, in both normal [8,9] and fatty livers.…”

“…The Apoptosis Signal-Regulating Kinase 1 (ASK1) is a master and upstream inductor of IRI in liver and in extrahepatic tissues [7][8][9] and both OS and ER stress are among the 2 of 12 factors that are able to induce ASK1 stimulation [7,9]. Consistently, we previously showed that the increased damage and inflammation of fatty liver that is exposed to IR is directly related to an enhanced ASK1 activation [10].…”

“…ASK1 signaling is modulated by multiple factors and stressful conditions and oxidative species are among the damaging conditions that have been proven to stimulate ASK1 [7][8][9]. Several proteins are also known to interact with ASK1 and to negatively or positively regulate its activity [7][8][9].…”

“…ASK1 signaling is modulated by multiple factors and stressful conditions and oxidative species are among the damaging conditions that have been proven to stimulate ASK1 [7][8][9]. Several proteins are also known to interact with ASK1 and to negatively or positively regulate its activity [7][8][9]. Among them, PI3K/Akt, the central signal mediators of the survival pathway that is activated upon A2AR activation [19,24], has been established to decrease ASK1 activity by phosphorylating a consensus Akt site at serine 83 [25].…”

“…The employment of inhibitors of ASK1 or JNK with human patients would be, however, problematic because of the multiple physio-pathological roles of these kinases. ASK1 acts, in fact, as a broad sensor of potentially damaging conditions and its blockage would induce a general inhibition of tissue capacity to respond to different stresses [7][8][9]. On the other hand, JNK was proven to exert toxic but also pro-survival effects and its blockage would avoid the protective outcomes of its activity [9,10].…”