The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway
The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway
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脂肪因子 orosumucoid 通过 AMPK 途径减轻脂肪组织纤维化
DOI：
10.1038/s41401-021-00666-9
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发表时间：
2021-04
影响因子：
8.2
通讯作者：
Xia Liu
中科院分区：
文献类型：
--
作者：
Peng-yuan Wang;Jia-yi Feng;Zhen Zhang;Yi Chen;Zhen Qin;Xian-min Dai;Jie Wei;Bo-han Hu;Wei-dong Zhang;Yang Sun;Xia Liu
脂肪组织中潜在的细胞外基质（ECM）的过度沉积被定义为脂肪组织纤维化，其是代谢紊乱如肥胖和2型糖尿病的主要促成因素。抗纤维化治疗在代谢性疾病的治疗中受到了广泛关注。Orosomucoid（ORM）是一种主要由肝脏产生的急性时相蛋白，也是一种脂肪因子。在本研究中，我们研究了ORM对脂肪组织纤维化的影响及其可能的机制。我们发现，ORM 1缺陷小鼠表现出肥胖表型，表现为脂肪组织中过度的胶原沉积和ECM调节剂如金属蛋白酶（MMP-2，MMP-13，MMP-14）和金属蛋白酶组织抑制剂（TIMP-1，TIMP-2，TIMP-3）的表达升高。在高脂饮食（HFD）喂养的小鼠和瘦素受体（LepR）缺乏的db/db小鼠中连续7天给予外源性ORM（50 mg· kg-1· d-1，ip）可减弱这些异常表达。同时，ORM刺激小鼠脂肪组织中AMPK磷酸化，降低转化生长因子β1（TGF-β1）水平。在TGF-β1处理的3 T3-L1成纤维细胞中，ORM（10 μg/mL）改善了纤维化相关基因受损的表达谱，而选择性AMPK抑制剂dorsomorphin（1 μmol/mL）消除了这些作用。总之，我们的研究结果表明，ORM通过AMPK激活在脂肪组织中发挥直接的抗纤维化作用。ORM有望成为治疗脂肪组织纤维化的新靶点。
The excess deposition of underlying extracellular matrix (ECM) in adipose tissue is defined as adipose tissue fibrosis that is a major contributor to metabolic disorder such as obesity and type 2 diabetes. Anti-fibrosis therapy has received much attention in the treatment of metabolic disorders. Orosomucoid (ORM) is an acute-phase protein mainly produced by liver, which is also an adipokine. In this study, we investigated the effects of ORM on adipose tissue fibrosis and the potential mechanisms. We showed that ORM1-deficient mice exhibited an obese phenotype, manifested by excessive collagen deposition in adipose tissues and elevated expression of ECM regulators such as metalloproteinases (MMP-2, MMP-13, MMP-14) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3). Administration of exogenous ORM (50 mg· kg−1· d−1, ip) for 7 consecutive days in high-fat diet (HFD)-fed mice and leptin receptor (LepR)-deficientdb/dbmice attenuated these abnormal expressions. Meanwhile, ORM administration stimulated AMP-activated protein kinase (AMPK) phosphorylation and decreased transforming growth factor-β1 (TGF-β1) level in adipose tissues of the mice. In TGF-β1-treated 3T3-L1 fibroblasts, ORM (10 μg/mL) improved the impaired expression profiles of fibrosis-related genes, whereas a selective AMPK inhibitor dorsomorphin (1 μmol/mL) abolished these effects. Together, our results suggest that ORM exerts a direct anti-fibrosis effect in adipose tissue via AMPK activation. ORM is expected to become a novel target for the treatment of adipose tissue fibrosis.
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影响因子：
5.8
作者：
Lin, De;Chun, Tae-Hwa;Kang, Li
通讯作者：
Kang, Li
影响因子：
4.8
作者：
Gunnarsson, Peter;Levander, Louise;Grenegard, Magnus
通讯作者：
Grenegard, Magnus
影响因子：
5.6
作者：
Qin Z;Wan JJ;Sun Y;Wang PY;Su DF;Lei H;Liu X
通讯作者：
Liu X
DOI：
10.1016/j.omtn.2017.07.004
发表时间：
2017-09-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Qi H;Liu Y;Li S;Chen Y;Li L;Cao Y;E M;Shi P;Song C;Li B;Sun H
通讯作者：
Sun H
影响因子：
9.6
作者：
M. Roy;P. Carey
通讯作者：
M. Roy;P. Carey