Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway.
Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway.
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Depdc5 缺乏通过抑制 PPAR α 通路加剧酒精诱导的肝脂肪变性
DOI：
10.1038/s41419-021-03980-6
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发表时间：
2021-07-15
影响因子：
9
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Xu L;Zhang X;Xin Y;Ma J;Yang C;Zhang X;Hou G;Dong XC;Sun Z;Xiong X;Cao X
酒精相关性肝病（ALD）是一种由酒精过度消费引起的疾病，发生在肝损伤的三个阶段，包括脂肪变性，肝炎和肝硬化。含DEP结构域蛋白5（DEP domain-containing protein 5，DEPDC 5）是雷帕霉素靶蛋白复合物1（mTOR 1）通路的氨基酸敏感分支的阻遏物，是GATOR 1复合物的GAP活性组分。在目前的研究中，我们发现mTORC 1的异常激活可能归因于乙醇喂养小鼠或ALD患者肝脏中DEPDC 5的减少。为了进一步确定DEPDC 5在ALD发展中的体内作用，我们产生了Depdc 5肝细胞特异性敲除小鼠模型（Depdc 5-LKO），其中mTORC 1通路通过GATOR 1的抑制作用的丧失而组成性激活。肝脏Depdc 5消融导致轻度肝肿大和肝损伤，并防止饮食诱导的肝脏脂肪变性。相比之下，乙醇喂养的Depdc 5-LKO小鼠发生了严重的肝脏脂肪变性和炎症。Torin 1的药物干预抑制了mTORC 1活性，并显着改善了对照和Depdc 5-LKO小鼠中乙醇诱导的肝脏脂肪变性和炎症。ALD中持续mTORC 1活性的病理学效应可能归因于过氧化物酶体增殖物激活受体α（PPARα）的抑制，这是肝细胞中脂肪酸氧化的主要调节因子，因为非诺贝特（PPARα激动剂）治疗逆转了Depdc 5-LKO小鼠中乙醇诱导的肝脏脂肪变性和炎症。这些发现为肝脏DEPDC 5在ALD发展中的体内作用提供了新的见解。
Alcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.
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影响因子：
29
作者：
Umemura A;Park EJ;Taniguchi K;Lee JH;Shalapour S;Valasek MA;Aghajan M;Nakagawa H;Seki E;Hall MN;Karin M
通讯作者：
Karin M
DOI：
10.1002/hep.28322
发表时间：
2016-02
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Burza MA;Motta BM;Mancina RM;Pingitore P;Pirazzi C;Lepore SM;Spagnuolo R;Doldo P;Russo C;Lazzaro V;Fischer J;Berg T;Aghemo A;Cheroni C;De Francesco R;Fargion S;Colombo M;Datz C;Stickel F;Valenti L;Romeo S
通讯作者：
Romeo S
影响因子：
29
作者：
Lamming DW;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.8
作者：
Liu, Qingsong;Kirubakaran, Sivapriya;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
4
作者：
Baldassari, Sara;Licchetta, Laura;Pippucci, Tommaso
通讯作者：
Pippucci, Tommaso