p38α MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure.
p38α MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure.
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p38 α MAPK 拮抗 JNK 控制肠衰竭儿科患者的肝脏脂肪堆积
DOI：
10.1038/cddis.2017.523
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发表时间：
2017-10-12
影响因子：
9
通讯作者：
Cai W
中科院分区：
文献类型：
--
作者：
Xiao Y;Wang J;Yan W;Zhou K;Cao Y;Cai W
p38α 丝裂原激活蛋白激酶 (MAPK) 与糖异生和脂质代谢有关。然而，p38α MAPK 在肠衰竭（IF）相关肝脂肪变性中的作用和相关机制仍知之甚少。在这里，我们的实验证据表明，p38α MAPK 主要通过两种机制显着抑制 IF 患者肝脏中的脂肪积累。一方面，p38α MAPK 通过上调限速酶胆固醇 7-α-羟化酶 (CYP7A1) 和过氧化物酶体增殖物激活受体 γ 辅激活因子-1α (PGC-1α) 的表达来增加肝胆汁酸 (BA) 合成，进而激活 CYP7A1 的转录。另一方面，p38α MAPK 通过上调过氧化物酶体增殖物激活受体 α (PPARα) 及其转录靶基因肉毒碱棕榈酰转移酶 1A (CPT1A) 和过氧化物酶体酰基辅酶氧化酶 1 (ACOX1) 促进脂肪酸 (FA) β-氧化。双荧光素酶测定表明，p38α MAPK 通过上调 PPARα、PGC-1α 和 CYP7A1 启动子的活性来增加其转录。此外，体外和体内试验表明 p38α MAPK 通过控制 JNK 激活来负向调节肝脏脂肪变性。总之，我们的研究结果表明，肝脏 p38α MAPK 通过拮抗 c-Jun N 末端激酶 (JNK) 作为肝脏脂肪变性的负调节因子，维持 BA 合成和 FFA。
The p38α mitogen-activated protein kinase (MAPK) has been related to gluconeogenesis and lipid metabolism. However, the roles and related mechanisms of p38α MAPK in intestinal failure (IF)-associated liver steatosis remained poor understood. Here, our experimental evidence suggested that p38α MAPK significantly suppressed the fat accumulation in livers of IF patients mainly through two mechanisms. On the one hand, p38α MAPK increased hepatic bile acid (BA) synthesis by upregulating the expression of the rate-limiting enzyme cholesterol 7-α-hydroxylase (CYP7A1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which in turn activated the transcription of the CYP7A1. On the other hand, p38α MAPK promoted fatty acid (FA) β-oxidation via upregulating peroxisome proliferator-activated receptor alpha (PPARα) and its transcriptional target genes carnitine palmitoyltransferase 1A (CPT1A) and peroxisomal acyl-coenzyme aoxidase 1 (ACOX1). Dual luciferase assays indicated that p38α MAPK increased the transcription of PPARα, PGC-1α and CYP7A1 by upregulating their promoters’ activities. In addition, in vitro and in vivo assays indicated p38α MAPK negatively regulates the hepatic steatosis by controlling JNK activation. In conculsion, our findings demonstrate that hepatic p38α MAPK functions as a negative regulator of liver steatosis in maintaining BA synthesis and FAO by antagonizing the c-Jun N-terminal kinase (JNK).
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影响因子：
30.8
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
影响因子：
1.7
作者：
Beeson, Craig C.;Beeson, Gyda C.;Muise-Helmericks, Robin C.
通讯作者：
Muise-Helmericks, Robin C.
影响因子：
3.1
作者：
Nehra, Deepika;Fallon, Erica M.;Puder, Mark
通讯作者：
Puder, Mark
影响因子：
4.3
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
肝脏中胆固醇7alpha-羟化酶在肝脏中的转基因表达可防止小脂饮食诱导的肥胖和胰岛素抵抗。
影响因子：
13.5
作者：
Li, Tiangang;Owsley, Erika;Matozel, Michelle;Hsu, Peter;Novak, Colleen M.;Chiang, John Y. L.
通讯作者：
Chiang, John Y. L.