Acetaminophen(APAP)is one of the major causes of drug-induced acute liver injury,and ethanol may aggravate APAP-induced liver injury.The problem of ethanol-and APAP-induced liver injury becomes increasingly prominent,but the mechanism of ethanol-and APAP-induced liver injury remains ambiguous.p38y is one of the four isoforms of P38 mitogen activated protein kinases,that contributes to inflammation in different diseases.In this study we investigated the role of p38y in ethanol-and APAP-induced liver injury.Liver injury was induced in male C57BL/6J mice by giving liquid diet containing 5％ethanol(v/v)for 10 days,followed by gavage of ethanol(25％(v/v),6 g/kg)once or injecting APAP(200 mg/kg,ip),or combined the both treatments.We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6J mice.Moreover,the expression level of p38y was up-regulated in the liver of ethanol-,APAP-and ethanol+APAP-treated mice.Knockdown of p38y markedly attenuated liver injury,inflammation,and steatosis in ethanol+APAP-treated mice.Liver sections of p38y-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes.AML-12 cells were exposed to APAP(5 mM),ethanol(100 mM)or combined treatments.We showed that P38y was markedly increased in ethanol+APAP-treated AML-12 cells,whereas knockdown of p38y significantly inhibited inflammation,lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells.Furthermore,we revealed that p38y could combine with Dlg1,a member of membrane-associated guanylate kinase family.Deletion of p38y up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells.In summary,our results suggest that p38y functions as an important regulator in ethanol-and APAP-induced liver injury through modulation of Dig1.

Shuang Hu;Yan Yao;Ze-yuan Wei;Shu-xian Wang;Yin-cui Wu;Ying Hu;Chen-chen Yang;Jing-li Min;Liang-yun Li;Hong Zhou;Jun-fa Yang;Jun Li;Tao Xu

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province,Anhui Institute of Innovative Drugs,School of Pharmacy,Anhui Medical University,Hefei 230032,China;Institute for Liver Diseases of Anhui Medical University,Hefei 230032,China

中国药理学报（英文版）

[1]Shuang Hu;Yan Yao;Ze-yuan Wei;Shu-xian Wang;Yin-cui Wu;Ying Hu;Chen-chen Yang;Jing-li Min;Liang-yun Li;Hong Zhou;Jun-fa Yang;Jun Li;Tao Xu-.Deletion of p38γ attenuates ethanol consumption-and acetaminophen-induced liver injury in mice through promoting Dlg1)[J].中国药理学报（英文版）,2022(07):1733-1748

Dlg1,p38y,ethanol+APAP,P38y,Dig1

Deletion,attenuates,consumption,acetaminophen,induced,liver,injury,mice,through,promoting,Acetaminophen,one,major,causes,drug,acute,may,problem,becomes,increasingly,prominent,mechanism,remains,ambiguous,four,isoforms,mitogen,activated,protein,kinases,that,contributes,inflammation,different,diseases,In,this,study,investigated,role,Liver,was,male,C57BL,6J,by,giving,liquid,diet,containing,days,followed,gavage,once,injecting,combined,both,treatments,We,showed,significantly,aggravated,Moreover,expression,up,regulated,treated,Knockdown,markedly,attenuated,steatosis,sections,knockdown,displayed,lower,levels,Oil,Red,stained,dots,small,leaky,shapes,AML,cells,were,exposed,mM,increased,whereas,inhibited,lipid,accumulation,oxidative,stress,Furthermore,revealed,could,member,membrane,associated,guanylate,family,summary,results,suggest,functions,important,regulator,modulation

0.399649