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Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids

Nature Medicine volume 18, pages 235–243 (2012)Cite this article

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Abstract

Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPβ onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBPβ to regulate expression of a subset of C/EBPβ downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPβ in mammary glands to control lipid secretion and pup survival.

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Figure 1: Cidea is expressed at higher levels in mammary glands of pregnant and lactating mice.
Figure 2: Impaired milk lipid secretion in lactating Cidea−/− female mice.
Figure 3: Cidea controls lipid secretion by regulating XOR expression.
Figure 4: Cidea interacts with C/EBPβ and activates the Xdh promoter.
Figure 5: Cidea and Fsp27 are localized to the nucleus.
Figure 6: Cidea binds to promoters of a subset of C/EBPβ target genes and enhances the DNA binding affinity of C/EBPβ.

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Acknowledgements

We thank L. Yu, L. Huang, Y. Hong and Y. Zhou for helpful discussions, and B. Groner (Georg-Speyer-Haus Institute for Biomedical Research) for providing HC11 cells. This work was supported by grants from the National Basic Research Program (2007CB914404, 2011CB910800) from the Ministry of Science and Technology of China and the National Natural Science Foundation of China (30925017 and 31030038 to P.L., 90913024 to Y.S.), and from the National University of Singapore and the Singapore National Research Foundation under CRP award no. 2007-04 to M.R.W.

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Authors and Affiliations

  1. Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

    Wenshan Wang, Na Lv, Shasha Zhang, Hui Qian, Jingfeng Zhang, Yuanying Chen & Peng Li

  2. Department of Biochemistry, and Department of Biological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Guanghou Shui & Markus R Wenk

  3. Department of Pathology, The Fourth Military Medical University, Xi'an, Shaanxi, China

    Jing Ye

  4. The State Key Laboratory of Kidney Disease, Institute of Nephrology, Chinese PLA General Hospital, Beijing, China

    Yuansheng Xie

  5. School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China

    Yuemao Shen

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Contributions

W.W. devised the hypothesis, designed and performed the experiments, analyzed the data and wrote the first draft of manuscript. N.L., S.Z., J.Z., H.Q. and Y.C. performed the experiments. G.S., M.R.W. performed lipidomics analysis. J.Y. performed EM analysis. Y.X. and Y.S. helped with experimental design and data analysis. P. L. is responsible for the formulation of the hypothesis, experimental design, data coordination, analysis and interpretation. P.L. is also responsible for the writing, revision and finalization of the manuscript as well as for the decision to submit the manuscript for publication. All authors read and approved the final manuscript.

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Correspondence to Peng Li.

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Wang, W., Lv, N., Zhang, S. et al. Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids. Nat Med 18, 235–243 (2012). https://doi.org/10.1038/nm.2614

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