Ccdc3: A new P63 target involved in regulation of liver lipid metabolism

Wenjuan Liao, Hongbing Liu, Yiwei Zhang, Ji Hoon Jung, Jiaxiang Chen, Xiaohua Su, Yeong C. Kim, Elsa R. Flores, San Ming Wang, Malwina Czarny-Ratajczak, Wen Li, Shelya X. Zeng, Hua Lu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

Original languageEnglish (US)
Article number9020
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Lipid Metabolism
Lipogenesis
Liver
High Fat Diet
Peroxisome Proliferator-Activated Receptors
Brown Adipose Tissue
Glucose Intolerance
Ceramides
Metformin
Liver Neoplasms
Unsaturated Fatty Acids
Adipocytes
Energy Metabolism
Genes
Insulin Resistance
Up-Regulation
Tumor Necrosis Factor-alpha
Fibroblasts
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • General

Cite this

Liao, W., Liu, H., Zhang, Y., Jung, J. H., Chen, J., Su, X., ... Lu, H. (2017). Ccdc3: A new P63 target involved in regulation of liver lipid metabolism. Scientific reports, 7(1), [9020]. https://doi.org/10.1038/s41598-017-09228-8

Ccdc3 : A new P63 target involved in regulation of liver lipid metabolism. / Liao, Wenjuan; Liu, Hongbing; Zhang, Yiwei; Jung, Ji Hoon; Chen, Jiaxiang; Su, Xiaohua; Kim, Yeong C.; Flores, Elsa R.; Wang, San Ming; Czarny-Ratajczak, Malwina; Li, Wen; Zeng, Shelya X.; Lu, Hua.

In: Scientific reports, Vol. 7, No. 1, 9020, 01.12.2017.

Research output: Contribution to journalArticle

Liao, W, Liu, H, Zhang, Y, Jung, JH, Chen, J, Su, X, Kim, YC, Flores, ER, Wang, SM, Czarny-Ratajczak, M, Li, W, Zeng, SX & Lu, H 2017, 'Ccdc3: A new P63 target involved in regulation of liver lipid metabolism', Scientific reports, vol. 7, no. 1, 9020. https://doi.org/10.1038/s41598-017-09228-8
Liao, Wenjuan ; Liu, Hongbing ; Zhang, Yiwei ; Jung, Ji Hoon ; Chen, Jiaxiang ; Su, Xiaohua ; Kim, Yeong C. ; Flores, Elsa R. ; Wang, San Ming ; Czarny-Ratajczak, Malwina ; Li, Wen ; Zeng, Shelya X. ; Lu, Hua. / Ccdc3 : A new P63 target involved in regulation of liver lipid metabolism. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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abstract = "TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.",
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