Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress.
Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress.
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DOI：
10.1038/s41419-023-06095-2
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发表时间：
2023-09-02
影响因子：
9
通讯作者：
Chen, Fengling
中科院分区：
文献类型：
--
作者：
Mao, Ziming;Ma, Xiaowen;Jing, Yu;Shen, Minyan;Ma, Xirui;Zhu, Jing;Liu, Huifang;Zhang, Guangya;Chen, Fengling
非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病，其特征在于脂质积聚和内质网（ER）应激，而针对NAFLD的特定特征的有效治疗是有限的。Ufmylation是一种新发现的翻译后修饰过程，它涉及UFM1蛋白通过Ufmylation修饰系统与底物的连接。Ufmylation通过修饰UFM1结合蛋白1（UFBP1）调节ER应激，提示Ufmylation在NAFLD发病机制中的潜在作用。然而，ufmylation在NAFLD中的确切作用仍不清楚。在此，我们的目的是阐明UFBP1在NAFLD中的ufmylation的影响，并探讨相关的潜在机制。我们观察到NAFLD患者和NAFLD模型脂肪变性肝脏中UFM1结合蛋白和UFM1修饰系统组分的表达增加。肝脏蛋白质的Ufmylation上调似乎是NAFLD对肝脏ER应激的适应性反应。在体外，敲低UFBP1导致用游离脂肪酸（FFA）处理的肝细胞中脂质积累和脂肪生成增加，这可以被野生型UFBP1（WT UFBP1）拯救，但不能被缺乏主要ufmylation位点lys267的UFBP1突变形式（UFBP1 K267 R）拯救。在体内，UFBP1的ufmylation改善了高脂饮食（HFD）诱导的NAFLD小鼠的肥胖、肝脂肪变性、肝脂肪生成、血脂异常、胰岛素抵抗和肝损伤。我们还证明，下调UFBP1诱导ER应激，而UFBP1的重新引入或过表达以依赖于NAFLD中的ufmylation的方式减轻ER应激。这一机制可能与改善NAFLD中异常的肝脏脂肪生成和胰岛素抵抗有关。我们的数据揭示了UFBP1上的ufmylation对NAFLD的保护作用，并为NAFLD治疗提供了一个特定的靶点。
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease characterized by lipid accumulation and endoplasmic reticulum (ER) stress, while effective therapies targeting the specific characteristics of NAFLD are limited. Ufmylation is a newly found post-translational modification process that involves the attachment of the Ubiquitin-fold modifier 1 (UFM1) protein to its substrates via ufmylation modification system. Ufmylation regulates ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in NAFLD pathogenesis. However, the precise role of ufmylation in NAFLD remains unclear. Herein, we aim to elucidate the impact of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms involved. We observed increased expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models. Upregulation of ufmylation on hepatic proteins appeared to be an adaptive response to hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 resulted in increased lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by wild-type UFBP1 (WT UFBP1) but not by a mutant form of UFBP1 lacking the main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in mice with NAFLD induced by a high fat diet (HFD). We also demonstrated that the downregulation of UFBP1 induced ER stress, whereas the reintroduction or overexpression of UFBP1 alleviated ER stress in a manner dependent on ufmylation in NAFLD. This mechanism could be responsible for the amelioration of aberrant hepatic lipogenesis and insulin resistance in NAFLD. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.
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影响因子：
4.5
作者：
Flores YN;Amoon AT;Su B;Velazquez-Cruz R;Ramírez-Palacios P;Salmerón J;Rivera-Paredez B;Sinsheimer JS;Lusis AJ;Huertas-Vazquez A;Saab S;Glenn BA;May FP;Williams KJ;Bastani R;Bensinger SJ
通讯作者：
Bensinger SJ
在条件X-box结合蛋白-1（XBP1）敲除小鼠中，从肝胰岛素抵抗中从肝胰岛素抵抗中解离肌醇提取酶（IRE1α）介导的C-JUN N末端激酶激活。
DOI：
10.1074/jbc.m111.316760
发表时间：
2012-01-20
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jurczak MJ;Lee AH;Jornayvaz FR;Lee HY;Birkenfeld AL;Guigni BA;Kahn M;Samuel VT;Glimcher LH;Shulman GI
通讯作者：
Shulman GI
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
15.9
作者：
Donnelly, KL;Smith, CI;Parks, EJ
通讯作者：
Parks, EJ
影响因子：
11.4
作者：
Komatsu, M;Chiba, T;Tanaka, K
通讯作者：
Tanaka, K