ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis.
ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis.
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DOI：
10.1016/j.jhep.2014.06.009
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发表时间：
2014-11
影响因子：
25.7
通讯作者：
Garcia-Ruiz, Carmen
中科院分区：
文献类型：
--
作者：
Fucho, Raquel;Martinez, Laura;Baulies, Anna;Torres, Sandra;Tarrats, Nuria;Fernandez, Anna;Ribas, Vicente;Astudillo, Alma M.;Balsinde, Jesus;Garcia-Roves, Pablo;Elena, Montserrat;Bergheim, Ina;Lotersztajn, Sophie;Trautwein, Christian;Appelqvist, Hanna;Paton, Adrienne W.;Paton, James C.;Czaja, Mark J.;Kaplowitz, Neil;Fernandez-Checa, Jose C.;Garcia-Ruiz, Carmen
酸性鞘磷脂酶（ASMase）在非酒精性脂肪性肝炎（NASH）中激活。然而，ASMase对NASH的作用知之甚少，仅限于肝脂肪变性和葡萄糖代谢。在这里，我们研究了ASMase在高脂肪饮食（HFD）诱导的NASH中的作用。研究了饲喂HFD的ASMase - / -小鼠的自噬、内质网（ER）应激和溶酶体膜通透性（LMP）。在饲喂HFD的野生型小鼠中分析ASMase药理抑制对NASH的影响。ASMase缺乏决定了对HFD或蛋氨酸和胆碱缺乏饮食介导的肝脂肪变性的抵抗力。ASMase - / -小鼠对hfd诱导的肝脏内质网应激具有抗性，但对tunicamycin介导的内质网应激和脂肪变性敏感，表明ASMase - / -小鼠对内质网应激的抗性具有选择性。在雷帕霉素和/或氯喹存在的情况下，ASMase - / -小鼠的原代小鼠肝细胞（PMH）的自噬通量较低，并伴有p62水平升高，提示自噬损伤。此外，氯喹和brefeldinA抑制自噬可引起ASMase+/+小鼠PMH内质网应激，而非ASMase - / -小鼠。ASMase - / - PMH表现出由o -甲基丝氨酸十二烷基酰胺盐酸盐或棕榈酸诱导的溶酶体胆固醇负荷增加、LMP降低和细胞凋亡抵抗，这些作用通过25-羟基胆固醇降低胆固醇水平而逆转。阿米替林（一种广泛使用的三环抗抑郁药）在体内抑制ASMase，可以保护野生型小鼠免受hfd诱导的肝脂肪变性、纤维化和肝损伤，这些作用表明早期NASH的存在。这些发现强调了ASMase在饮食诱导的NASH中的关键作用，并提示阿米替林作为NASH患者治疗的潜力。
Acid sphingomyelinase (ASMase) is activated in nonalcoholic steatohepatitis (NASH). However, ASMase’s contribution to NASH is poorly understood and limited to hepatic steatosis and glucose metabolism. Here we examined ASMase’s role in high fat diet (HFD)-induced NASH. Autophagy, endoplasmic reticulum (ER) stress and lysosomal membrane permeabilization (LMP) were determined in ASMase−/− mice fed HFD. The impact of pharmacological ASMase inhibition on NASH was analyzed in wild type mice fed HFD. ASMase deficiency determined resistance to HFD or methionine and choline deficient diet-mediated hepatic steatosis. ASMase−/− mice were resistant to HFD-induced hepatic ER stress, but sensitive to tunicamycin-mediated ER stress and steatosis, indicating selectivity in the resistance of ASMase−/− mice to ER stress. Autophagic flux determined in the presence of rapamycin and/or chloroquine was lower in primary mouse hepatocytes (PMH) from ASMase−/− mice and accompanied by increased p62 levels, suggesting autophagic impairment. Moreover, autophagy suppression by chloroquine and brefeldinA caused ER stress in PMH from ASMase+/+ mice but not ASMase−/− mice. ASMase−/− PMH exhibited increased lysosomal cholesterol loading, decreased LMP and apoptosis resistance induced by O-methyl-serine dodecylamide hydrochloride or palmitic acid, effects that were reversed by decreasing cholesterol levels by the oxysterol 25-hydroxycholesterol. In vivo pharmacological ASMase inhibition by amitriptyline, a widely used tricyclic antidepressant, protected wild type mice against HFD-induced hepatic steatosis, fibrosis, and liver damage, effects indicative of early-stage NASH. These findings underscore a critical role for ASMase in diet-induced NASH and suggest the potential of amitriptyline as a treatment for patients with NASH.
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影响因子：
29
作者：
Dong S;Jia C;Zhang S;Fan G;Li Y;Shan P;Sun L;Xiao W;Li L;Zheng Y;Liu J;Wei H;Hu C;Zhang W;Chin YE;Zhai Q;Li Q;Liu J;Jia F;Mo Q;Edwards DP;Huang S;Chan L;O'Malley BW;Li X;Wang C
通讯作者：
Wang C
影响因子：
6
作者：
Appelqvist, Hanna;Nilsson, Cathrine;Ollinger, Karin
通讯作者：
Ollinger, Karin
影响因子：
29
作者：
Mari, Montserrat;Caballero, Francisco;Garcia-Ruiz, Carmen
通讯作者：
Garcia-Ruiz, Carmen
影响因子：
82.9
作者：
Lang, Philipp A.;Schenck, Marcus;Lang, Florian
通讯作者：
Lang, Florian
影响因子：
64.8
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.