Lipid oversupply induces CD36 sarcolemmal translocation via dual modulation of PKCζ and TBC1D1: an early event prior to insulin resistance.
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.
['Zhu|Bili|B|', 'Li|Ming-Yue|MY|', 'Lin|Quanming|Q|', 'Liang|Zhicheng|Z|', 'Xin|Qihang|Q|', 'Wang|Menghuan|M|', 'He|Zhendan|Z|', 'Wang|Xiaomei|X|', 'Wu|Xuli|X|', 'Chen|George G|GG|', 'Tong|Peter Cy|PC|', 'Zhang|Weizhen|W|', 'Liu|Li-Zhong|LZ|']
D000818:Animals D018955:CD36 Antigens D002460:Cell Line D003924:Diabetes Mellitus, Type 2 D059305:Diet, High-Fat D005227:Fatty Acids D020690:GTPase-Activating Proteins D007333:Insulin Resistance D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D032342:Muscle Cells D000074121:Protein Kinase C-theta D021381:Protein Transport D051381:Rats D012508:Sarcolemma
CD36 PKCζ TBC1D1 fatty acid