Cell Res. 2016 Jul;26(7):787-804. doi: 10.1038/cr.2016.75. Epub 2016 Jun 17.

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly.

Wang Y1, Liu L1,2, Zhang H1,2, Fan J1,2, Zhang F1,2, Yu M3, Shi L1, Yang L1, Lam SM1, Wang H4, Chen X4, Wang Y1, Gao F5, Shui G1, Xu Z1,6.
  • 1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 2University of Chinese Academy of Sciences, Beijing 100101, China.
  • 3School of Life Science, Shandong University, Jinan 250100, China.
  • 4Institute of Molecular Medicine, Peking University, Beijing 100871, China.
  • 5State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 6Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

 

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.

PMID: 27311593

 

Supplement:

Fat accumulation in the liver due to defects in lipoprotein assembly or transport would lead to fatty liver or hepatic steatosis. Fatty liver is one of the most prevalent forms of chronic liver disease worldwide. VLDL assembly and secretion from the liver plays a critical role in controlling the plasma levels of triacylglycerols (TGs) and cholesterol. However, the underlying molecular mechanism for VLDL assembly and export is still poorly understood.

Meningioma-expressed antigen 6 (Mea6), also known as cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C), has been shown to interact with TANGO1 for the transport of collagen VII (1). We found that high fat diet induced the expression of Mea6 in mice liver, indicating Mea6 might be involved in lipid metabolism. In order to examine the physiological function of Mea6, we knocked out Mea6 gene in mouse liver. Our data indicated that hepatocyte-specific deletion of Mea6 led to severe fatty liver and hypolipemia in mice. Figure 1 shows that lipid droplets accumulate in Mea6 conditional knockout (cKO) mice liver.

 

 

biomedical-frontier-figure

Figure 1. Primary cultured hepatocytes from control and Mea6 cKO mice stained with Bodipy493 and  antibody against Mea6. Note the sizes of lipid droplets are substantially larger in cKO hepatocytes.

 

Quantitative lipidomic and proteomic analyses indicate that Mea6 deletion impairs the secretion of different types of lipids and proteins, including VLDL, from the liver. Moreover, we demonstrate that Mea6 interacts with components of the ER coat protein complex II (COPII) which, when depleted, also cause lipid accumulation in hepatocytes. These 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. The paper featured at this site describes these studies (2).

Our findings provide novel insights into mechanisms underlying VLDL transportation. More importantly, the mouse model provides a useful tool for drug screening for the treatment of fatty liver.

 

References

  1. Saito K, Yamashiro K, Ichikawa Y, Erlmann P, Kontani K, Malhotra V, Katada T. 2011, cTAGE5 mediates collagen secretion through interaction with TANGO1 at endoplasmic reticulum exit sites. Mol Biol Cell 22:2301-2308.
  2. Wang Y, Liu L, Zhang H, Fan J, Zhang F, Yu M, Shi L, Yang L, Lam SM, Wang H, Chen X, Wang Y, Gao F, Shui G, Xu Z. 2016,    Mea6 controls VLDL transport through the coordinated regulation of COPII assembly. Cell Res 26(7):787-804.

 

Acknowledgements:  This study was supported by grants from National Natural Science Foundation of China (31430037/31471132/31270826/31271156) and the MOST (China) “973” program (2014CB942801/2012CB517904). 

 

Contact:

Zhiheng Xu

Professor State Key Laboratory of Molecular Developmental Biology,

Institute of Genetics and Developmental Biology,

Chinese Academy of Sciences, Beijing 100101, China;

zhxu@genetics.ac.cn

 

 

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