Abstract
Lipid accumulation, which may be caused by the disturbance in very low density lipoprotein (VLDL) secretion in the liver, can lead to fatty liver disease. VLDL is synthesized in endoplasmic reticulum (ER) and transported to Golgi apparatus for secretion into plasma. However, the underlying molecular mechanism for VLDL transport is still poorly understood. Here we show that hepatocyte-specific deletion of meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) leads to severe fatty liver and hypolipemia in mice. Quantitative lipidomic and proteomic analyses indicate that Mea6/cTAGE5 deletion impairs the secretion of different types of lipids and proteins, including VLDL, from the liver. Moreover, we demonstrate that Mea6/cTAGE5 interacts with components of the ER coat protein complex II (COPII) which, when depleted, also cause lipid accumulation in hepatocytes. Our findings not only reveal several novel factors that regulate lipid transport, but also provide evidence that Mea6 plays a critical role in lipid transportation through the coordinated regulation of the COPII machinery.
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Acknowledgements
We would like to thank Dr Sidney Yu for providing constructs, Drs WZ Jin, X Huang, BL Song and P. Li for their constructive comments, Miss Xiahe Huang at IGDB for help with mass spectrometry analysis. This work was supported in part by grants from the NSF (China) (31430037/31471132/31270826/31271156) and the MOST (China) “973” program (2014CB942801/2012CB517904).
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Supplementary information
Supplementary information, Figure S1
Characterization of Mea6 6cKO cKO mouse. (PDF 164 kb)
Supplementary information, Figure S2
Body weight and liver histological analysis. (PDF 312 kb)
Supplementary information, Figure S3
Reduced VLDL secretion but normal albumin and glucose secretion, normal lipid synthesis and normal total protein secretion in Mea6 knockout mice. (PDF 84 kb)
Supplementary information, Figure S4
mRNA levels of different genes involved in lipid metabolism in P1 and P35 livers. (PDF 87 kb)
Supplementary information, Figure S5
Mea6 does not interact with Sec24C but interacts indirectly with Sec31A. (PDF 97 kb)
Supplementary information, Figure S6
Knockdown of Mea6, Sec23A, Sec24D and Sec31A caused LDs accumulation in Bel7402 cells. (PDF 210 kb)
Supplementary information, Table S1
Primers for real-time analysis (PDF 177 kb)
Supplementary information, Table S2
Sequences of siRNA or shRNA (PDF 465 kb)
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Wang, Y., Liu, L., Zhang, H. et al. Mea6 controls VLDL transport through the coordinated regulation of COPII assembly. Cell Res 26, 787–804 (2016). https://doi.org/10.1038/cr.2016.75
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DOI: https://doi.org/10.1038/cr.2016.75
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