Cystathionine γ lyase-hydrogen sulfide increases peroxisome proliferator-activated receptor γ activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes
Cystathionine γ lyase-hydrogen sulfide increases peroxisome proliferator-activated receptor γ activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes
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胱硫醚γ裂解酶-硫化氢通过C139位点的硫化作用增加过氧化物酶体增殖物激活受体γ活性，从而促进脂肪细胞中的葡萄糖摄取和脂质储存
DOI：
10.1016/j.bbalip.2016.03.001
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发表时间：
2016-05-01
影响因子：
4.8
通讯作者：
Geng, Bin
中科院分区：
文献类型：
--
作者：
Cai, Junyan;Shi, Xiaoqin;Geng, Bin
脂肪细胞表达胱硫醚γ裂解酶（CSE）-硫化氢（H2S）系统。CSE-H2S促进脂肪生成，但改善脂肪细胞胰岛素抵抗。我们研究了CSE-H2S如何诱导这些矛盾效应的机制。首先，我们证实了H2S供体或CSE过表达促进脂肪细胞分化。第二，我们发现H_2S供体抑制磷酸二酯酶（PDE）活性，而CSE抑制则增加PDE活性。在分化程序中H2S取代异丁基甲基黄嘌呤部分诱导脂肪细胞分化。通过H2S抑制PDE活性诱导过氧化物酶体增殖物激活受体γ（PPAR γ）蛋白和mRNA表达。值得注意的是，H2S直接使PPAR γ蛋白巯基化。硫酸化的PPAR γ增加其核积累、DNA结合活性和脂肪形成基因表达，从而增加葡萄糖摄取和脂质储存，这被脱水试剂DTT阻断。H2S诱导的PPAR γ硫水合作用，这是由PPAR γ的C139位点的突变阻断。在喂食高脂饮食（HFD）4周的小鼠中，CSE抑制剂减少，但H2S供体增加脂肪细胞数量。在喂食HFD 13周的肥胖小鼠中，H2S治疗增加了脂肪组织中的PPAR γ硫水合作用，并减弱了胰岛素抵抗，但没有增加肥胖。总之，CSE-H2S通过C139位点的直接硫水合作用增加了PPAR γ活性，从而将葡萄糖转化为脂肪细胞中的甘油三酯储存。CSE-H2S介导的PPAR γ激活可能是肥胖相关糖尿病的新治疗靶点。(C)© 2016 Elsevier B.V.版权所有。
Adipocytes express the cystathionine gamma lyase (CSE)-hydrogen sulfide (H2S) system. CSE-H2S promotes adipogenesis but ameliorates adipocyte insulin resistance. We investigated the mechanism of how CSE-H2S induces these paradoxical effects. First, we confirmed that an H2S donor or CSE overexpression promoted adipocyte differentiation. Second, we found that H2S donor inhibited but CSE inhibition increased phosphodiesterase (PDE) activity. H2S replacing isobutylmethylxanthine in the differentiation program induced adipocyte differentiation in part. Inhibiting PDE activity by H2S induced peroxisome proliferator activated receptor gamma (PPAR gamma) protein and mRNA expression. Of note, H2S directly sulfhydrated PPAR gamma protein. Sulfhydrated PPAR gamma increased its nuclear accumulation, DNA binding activity and adipogenesis gene expression, thereby increasing glucose uptake and lipid storage, which were blocked by the desulfhydration reagent DTT. H2S induced PPAR gamma sulfhydration, which was blocked by mutation of the C139 site of PPAR gamma. In mice fed a high-fat diet (HFD) for 4 weeks, the CSE inhibitor decreased but H2S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H2S treatment increased PPAR gamma sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE-H2S increased PPAR gamma activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE-H2S-mediated PPAR gamma activation might be a new therapeutic target for diabetes associated with obesity. (C) 2016 Elsevier B.V. All rights reserved.