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.
Highlights
Liver, as a primary metabolic organ, plays a vital role in the regulation of lipid metabolism and is sensitive to energy intake and vulnerable to metabolic disorder-causing stressors or conditions
In searching for new INZ-responsive transcriptional targets of these p53 family members, we identify coiled coil domain-containing 3 (CCDC3) as a potential target of TAp63 through microarray analysis of RNAs extracted from cells treated with or without INZ
Because CCDC3 was previously shown to be highly expressed in mouse endothelial cells[9, 11], we tested if TAp63 could induce CCDC3 expression in normal endothelial cells using human umbilical vein endothelial cells (HUVEC)
Summary
As a primary metabolic organ, plays a vital role in the regulation of lipid metabolism and is sensitive to energy intake and vulnerable to metabolic disorder-causing stressors or conditions. Insulin resistance plays a major role in the development of NAFLD, while ectopic liver lipid exacerbates hepatic insulin resistance, promotes systemic inflammation, and increases the risk of developing both type 2 diabetes mellitus and cardiovascular disease[3, 4]. Several key metabolism regulators were identified as TAp63 direct targets, such as Sirt[1], AMPK, and LKB15, the precise molecular mechanisms underlying hepatic steatosis remain largely elusive. We identified the CCDC3-encoding gene as a novel target for TAp63, which is involved in lipid metabolism. 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
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