Oxidative and ER stress-dependent ASK1 activation in steatotic hepatocytes and Kupffer cells sensitizes mice fatty liver to ischemia/reperfusion injury

氧化应激 p38丝裂原活化蛋白激酶 ASK1 肝细胞 脂肪变性 化学 肝损伤 炎症 MAPK/ERK通路 内分泌学 内科学 生物 生物化学 医学 信号转导 激酶 蛋白激酶A 丝裂原活化蛋白激酶激酶 体外
作者
Chiara Imarisio,Elisa Alchera,Chandrashekar Bangalore Revanna,Guido Valente,Antonia Follenzi,Elena Trisolini,Renzo Boldorini,Rita Carini
出处
期刊:Free Radical Biology and Medicine [Elsevier BV]
卷期号:112: 141-148 被引量:42
标识
DOI:10.1016/j.freeradbiomed.2017.07.020
摘要

Steatosis intensifies hepatic ischemia/reperfusion (I/R) injury increasing hepatocyte damage and hepatic inflammation. This study evaluates if this process is associated to a differential response of steatotic hepatocytes (HP) and Kupffer cells (KC) to I/R injury and investigates the molecular mechanisms involved. Control or steatotic (treated with 50 μmol palmitic acid, PA) mouse HP or KC were exposed to hypoxia/reoxygenation (H/R). C57BL/6 mice fed 9 week with control or High Fat diet underwent to partial hepatic IR. PA increased H/R damage of HP and further activated the ASK1-JNK axis stimulated by ER stress during H/R. PA also induced the production of oxidant species (OS), and OS prevention nullified the capacity of PA to increase H/R damage and ASK1/JNK stimulation. ASK1 inhibition prevented JNK activation and entirely protected HP damage. In KC, PA directly activated ER stress, ASK1 and p38 MAPK and increased H/R damage. However, in contrast to HP, ASK1 inhibition further increased H/R damage by preventing p38 MAPK activation. In mice liver, steatosis induced the expression of activated ASK1 in only KC, whereas I/R exposure of steatotic liver activated ASK1 expression also in HP. “In vivo”, ASK1 inhibition prevented ASK1, JNK and p38 MAPK activation and protected I/R damage and expression of inflammatory markers. Lipids-induced ASK1 stimulation differentially affects HP and KC by promoting cytotoxic or protective signals. ASK1 increases H/R damage of HP by stimulating JNK and protects KC activating p38MAPK. These data support the potentiality of the therapeutic employment of ASK1 inhibitors that can antagonize the damaging effects of I/R upon fatty liver surgery by the contextual reduction of HP death and of KC-mediated reactions.
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