Lipid oversupply induces CD36 sarcolemmal translocation via dual modulation of PKCζ and TBC1D1: an early event prior to insulin resistance
Lipid oversupply induces CD36 sarcolemmal translocation via dual modulation of PKCζ and TBC1D1: an early event prior to insulin resistance
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脂质过度供应通过 PKCγ 和 TBC1D1 的双重调节诱导 CD36 肌膜易位：胰岛素抵抗之前的早期事件
DOI：
10.7150/thno.40021
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发表时间：
2020-01
期刊：
影响因子：
12.4
通讯作者：
Li-Zhong Liu
中科院分区：
文献类型：
--
作者：
Bili Zhu;Ming-Yue Li;Quanming Lin;Zhicheng Liang;Qihang Xin;Menghuan Wang;Zhendan He;Xiaomei Wang;Xuli Wu;George G. Chen;Peter CY Tong;Weizhen Zhang;Li-Zhong Liu
脂质供过于求可能会导致CD36肌膜易位，促进脂肪酸运输，进而导致血脂异常和2型糖尿病。然而，CD36再分布的潜在机制仍有待解开。方法：采用高脂饮食喂养的小鼠和经棕榈酸/油酸处理的L6细胞，研究胰岛素抵抗前亚细胞CD36循环的初始事件。采用胰岛素耐量试验(ITT)、口服葡萄糖耐量试验(OGTT)、葡萄糖/脂肪酸摄取试验、表面CD36和GLUT4检测及酶联免疫吸附试验等方法，评价脂质供应过剩对CD36肌膜转位的调节作用。采用特异性基因敲除、基因过表达和(或)基因抑制、免疫印迹、免疫共沉淀、免疫染色和蛋白激酶活性检测等方法对其作用机制进行了研究。结果：在脂质/脂肪酸超负荷时，随着肌膜CD36的增加，蛋白激酶Cζ活性和Tbc1d1的磷酸化增强。抑制PKCζ或TbC1d1可阻断脂肪酸诱导的CD36易位，并协同抑制CD36的再分布。力学上，我们发现AMPK位于PKCζ的上游，以控制其活性，而Rac1促进PKCζ易位到细胞背部表面，导致肌动蛋白重塑。此外，AMPK还能使TBC1D1磷酸化，释放胞浆内残留的CD36。活化的蛋白激酶Cζ和磷酸化的Tbc1d1对CD36肌膜转位具有正反馈调节作用。结论：总体而言，我们的研究仅证实了脂质过量通过对蛋白激酶Cζ和Tbc1d1的双重调节诱导了CD36肌膜易位，这是胰岛素抵抗之前的一个早期事件。所获得的数据可能为预防脂质过量引起的胰岛素抵抗提供潜在的治疗靶点。
Lipid oversupply may induce CD36 sarcolemmal translocation to facilitate fatty acid transport, which in turn causes dyslipidemia and type 2 diabetes. However, the underlying mechanisms of CD36 redistribution are still yet to be unraveled. Methods: High fat diet fed mice and palmitate/oleic acid-treated L6 cells were used to investigate the initial events of subcellular CD36 recycling prior to insulin resistance. The regulation of CD36 sarcolemmal translocation by lipid oversupply was assessed by insulin tolerance test (ITT), oral glucose tolerance test (OGTT), glucose/fatty acid uptake assay, surface CD36 and GLUT4 detection, and ELISA assays. To elucidate the underlying mechanisms, specific gene knockout, gene overexpression and/or gene inhibition were employed, followed by Western blot, co-immunoprecipitation, immunostaining, and kinase activity assay. Results: Upon lipid/fatty acid overload, PKCζ activity and TBC1D1 phosphorylation were enhanced along with increased sarcolemmal CD36. The inhibition of PKCζ or TBC1D1 was shown to block fatty acid-induced CD36 translocation and was synergistic in impairing CD36 redistribution. Mechanically, we revealed that AMPK was located upstream of PKCζ to control its activity whereas Rac1 facilitated PKCζ translocation to the dorsal surface of the cell to cause actin remodeling. Furthermore, AMPK phosphorylated TBC1D1 to release retained cytosolic CD36. The activated PKCζ and phosphorylated TBC1D1 resulted in a positive feedback regulation of CD36 sarcolemmal translocation. Conclusion: Collectively, our study demonstrated exclusively that lipid oversupply induced CD36 sarcolemmal translocation via dual modulation of PKCζ and TBC1D1, which was as an early event prior to insulin resistance. The acquired data may provide potential therapy targets to prevent lipid oversupply-induced insulin resistance.
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影响因子：
2.7
作者：
Takaaki Hirai;K. Chida
通讯作者：
Takaaki Hirai;K. Chida
DOI：
10.1007/s00018-011-0690-x
发表时间：
2011-08
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Steinbusch LK;Schwenk RW;Ouwens DM;Diamant M;Glatz JF;Luiken JJ
通讯作者：
Luiken JJ
影响因子：
7.7
作者：
Hardie DG
通讯作者：
Hardie DG
DHHC4 和 DHHC5 通过棕榈酰化和将 CD36 靶向质膜来促进脂肪酸摄取
影响因子：
8.8
作者：
Wang Juan;Hao Jian-Wei;Wang Xu;Guo Huiling;Sun Hui-Hui;Lai Xiao-Ying;Liu Li-Ying;Zhu Mingxia;Wang Hao-Yan;Li Yi-Fan;Yu Li-Yang;Xie Changchuan;Wang Hong-Rui;Mo Wei;Zhou Hai-Meng;Chen Shuai;Liang Guosheng;Zhao Tong-Jin
通讯作者：
Zhao Tong-Jin
影响因子：
8.2
作者：
Turner, N.;Kowalski, G. M.;Bruce, C. R.
通讯作者：
Bruce, C. R.