Coiled-coil domain containing 3 (CCDC3) represses tumor necrosis factor-α/nuclear factor κB-induced endothelial inflammation

Azad, Abul Kalam; Chakrabarti, Subhadeep; Xu, Zhihua; Davidge, Sandra T.; Fu, YangXin

doi:10.1016/j.cellsig.2014.08.025

Cited by 32 publications

(48 citation statements)

References 28 publications

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“…Interestingly, our study also suggests an anti-inflammation role for CCDC3, as we observed the marked reduction of F4/80 positive cells and the decrease of TNFα expression in CCDC3 TG liver tissues (Figs 6f ; 7g,i ). This anti-inflammation phenotype is in line with the previous study showing that CCDC3 decrease TNFα induced expression of vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells (ECs) 11 . TNFα has been shown to contribute to the insulin resistant state 44 , 45 .…”

Section: Discussionsupporting

confidence: 92%

“…1b and c ). Because CCDC3 was previously shown to be highly expressed in mouse endothelial cells 9 , 11 , we also tested if TAp63 could induce CCDC3 expression in normal endothelial cells using h uman u mbilical v ein e ndothelial c ells (HUVEC). Consistently with the results using cancer cells above, TAp63γ, but not p40, also induced the expression of CCDC3 mRNA in HUVEC (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CCDC3 mRNA expression in adipocytes and endothelial cells is regulated by hormones and nutritional factors 9 . A study showed that CCDC3 could repress TNF-α/NF-KB-induced a pro-inflammatory response in endothelial cells, suggesting a potential role for CCDC3 in the development of obesity and atherosclerosis 11 . As detailed below, our study using cellular analyses and two mouse model systems with ectopic CCDC3 expression unveils CCDC3 as an authentic transcriptional target of TAp63 to play a role in the regulation of liver lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

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

Liao

Liu

Zhang

et al. 2017

Sci Rep

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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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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Liao

Liu

Zhang

et al. 2017

Sci Rep

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“…The STARD13 gene has moreover been associated (P ≤ 1 9 10 À5 ) with plasma levels of amyloid beta peptides that, among other things, play a role in Alzheimer's disease and hypertension (Chouraki et al, 2014). In addition, also the CCDC3 and IRAK1BP1 genes could be speculated to play a role in human lifespan, as they have been reported to inhibit inflammation (Conner et al, 2008(Conner et al, , 2010Azad et al, 2014), and as revealed by the GO enrichment analysis, the majority of the other genes are involved in cell adhesion, which has previously been linked to longevity and age-related diseases (Wolfson et al, 2009;Tian et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

et al. 2015

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SummaryCopy number variants (CNVs) represent a significant source of genetic variation in the human genome and have been implicated in numerous diseases and complex traits. To date, only a few studies have investigated the role of CNVs in human lifespan. To investigate the impact of CNVs on prospective mortality at the extreme end of life, where the genetic component of lifespan appears most profound, we analyzed genomewide CNV data in 603 Danish nonagenarians and centenarians (mean age 96.9 years, range 90.0–102.5 years). Replication was performed in 500 long‐lived individuals from the Leiden Longevity Study (mean age 93.2 years, range 88.9–103.4 years). First, we assessed the association between the CNV burden of each individual (the number of CNVs, the average CNV length, and the total CNV length) and mortality and found a significant increase in mortality per 10 kb increase in the average CNV length, both for all CNVs (hazard ratio (HR) = 1.024, P = 0.002) and for duplications (HR = 1.011, P = 0.005), as well as per 100 kb increase in the total length of deletions (HR = 1.009, P = 0.0005). Next, we assessed the relation between specific deletions and duplications and mortality. Although no genome–wide significant associations were discovered, we identified six deletions and one duplication that showed consistent association with mortality in both or either of the sexes across both study populations. These results indicate that the genome–wide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long‐lived individuals.

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“…The number of vessels stained with CD31 (31), one of endothelial cell markers, in adipose tissue in Favine KO mice was not changed (data not shown). Recently Azad et al (32) showed that Favine represses tumor necrosis factor-␣-stimulated vascular cell adhesion molecule-1 expression in endothelial cells in vitro. Further investigation on the function of Favine in endothelial cells in vivo and in vitro will help with understanding the mechanism of physiological action of Favine.…”

Section: Discussionmentioning

confidence: 99%

Fat/Vessel-derived Secretory Protein (Favine)/CCDC3 Is Involved in Lipid Accumulation

Kobayashi

Fukuhara

Otsuki

et al. 2015

Journal of Biological Chemistry

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Background: Coiled-coil domain-containing 3 (Ccdc3) mRNA is highly expressed in adipose tissue and vessels, but its function remains unknown. Results: CCDC3 overexpression promoted adipogenesis of 3T3-L1 adipocytes, whereas CCDC3 deficiency reduced adiposity and inhibited age-related hepatic steatosis in mice. Conclusion: CCDC3 positively regulates lipid accumulation. Significance: CCDC3 is a possible therapeutic target to age-related obesity and diseases.

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Coiled-coil domain containing 3 (CCDC3) represses tumor necrosis factor-α/nuclear factor κB-induced endothelial inflammation

Cited by 32 publications

References 28 publications

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

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

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

Fat/Vessel-derived Secretory Protein (Favine)/CCDC3 Is Involved in Lipid Accumulation

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