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Sci Rep. 2017 Aug 21;7(1):9020. doi: 10.1038/s41598-017-09228-8.

Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism.

Author information

1
Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
2
Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
3
Department of Physiology, Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China.
4
Department of Molecular Oncology, Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.
5
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, 68198, NE, USA.
6
Faculty of Health Sciences, University of Macau, Macau, China.
7
Department of Medicine, Center for Aging, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
8
Laboratory of General Surgery, The First Affiliated Hospital, Sun Yatsen University, Guangzhou, Guangdong, 510080, P.R. China.
9
Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA. szeng@tulane.edu.
10
Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA. hlu2@tulane.edu.

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.

PMID:
28827783
PMCID:
PMC5566403
DOI:
10.1038/s41598-017-09228-8
[Indexed for MEDLINE]
Free PMC Article

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