学习：Cidea是调控milk lipids分泌的转录活化因子

wang2012

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

transcriptional coactivator 转录活化因子指的是细胞质中的转录因子接受来自细胞膜并逐渐传递进来的信号之后，通过磷酸化或脱磷酸化等作用而被活化．然后从胞质进入细胞核，与相应DNA框（顺式作用元件）结合。

摘要

在乳腺中，cidea高表达，cidea的缺乏会引起milk lipids的严重缺乏，进而导致早产premature pup death；
在cidea-deficiency的乳腺中，XOR（xanthine oxidoreductase）的表达会显著降低，XOR是一种影响分泌milik lipids的关键因子

• 我们在细胞核nucleus中检测到cidea蛋白（之前heretofore认为存在于胞质cytoplasmic中），还发现cidea蛋白和转录因子transcription factor CCAAT/enhancer-binding protein b (C/EBPb) 在乳房上皮细胞mammary epithelial cells中有physically interact；
• 同样观察到，Cidea induces XOR expression 一是通过促进C/EBP b 与Xdh基因（编码xanthine oxidoreductase（XOR））promoter的结合association ，二是促进 HDAC1从 Xdh gene的promoter上解离dissociation；
• 最终发现Fsp27, another CIDE family protein, is detected in the nucleus，在脂肪细胞adipocytes中，Fsp27 interacts with C/EBPb to regulate C/EBPb 部分下游基因的表达。
• Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPb in mammary glands to control lipid secretion and pup survival.

Intro

• 正常的lactation需要 mammary epithelial cells的proliferation and deferentiation，在此过程之中 mammary epithelial cells会形成lobuloalveolar structure（一种类似于肺泡的结构），标志着protein and lipid synthesis and secretion of milk。
• 在几种转基因小鼠模型中，泌乳性乳腺中乳脂分泌减少与新生儿存活率低有关。

- 在泌乳的乳腺中，lipid secretion分两步：

1. 顶质膜内胞浆脂质小滴（CLD）的包裹-the envelopment of cytosolic lipid droplets (CLDs) within the apical plasma membrane,
2. 然后以乳脂球（MFG）的形式发芽到乳腺泡腔中。-followed by budding out to the lumen of mammary alveoli as milk fat globules (MFGs).

- XOR：

1. XOR通常在乳腺上皮细胞的细胞质中扩散，当分泌被激活时，其位于顶膜上与丁酰尿素（BTN）的细胞质域相互作用。 XOR is usually diffused in the cytoplasm of mammary epithelial cells, is localized to the apical membrane to interact with the cytoplasmic domain of butyrophilin (BTN) when secretion is activated.
2. XOR，BTN和CLD上一些未知蛋白之间的相互作用促进了CLD的包封和MFG的萌芽 The interaction between XOR, BTN and some unknown proteins on CLDs promotes the envelopment of CLDs and their budding off as MFGs
3. 在pregnancy and lactation期间，XOR受到transcription factor C/EBPβ的调控，XOR的表达明显上调is markedly upregulated。

- CIDE-family proteins
ex：Cidea, Cideb and Fsp27 (Cidec)
Cidea is highly enriched in adult brown adipose tissue (BAT), and its deficiency results in

1. the accumulation of smaller lipid droplets,
2. improved insulin sensitivity and resistance to diet-induced obesity
   Here we show
3. Cidea is expressed at high levels in lactating mammary glands
4. its deficiency results in reduced milk lipid secretion and poor newborn survival.
5. Cidea is localized to the nucleus and interacts with C/EBPβ to enhance the expression of a subset of C/EBPβ downstream genes（including that encoding XOR, that controls milk lipid secretion.）

总结：乳腺上皮细胞nucleus中cidea与C/EBPβ作用后，促进C/EBPβ与Xdh基因（编码XOR）promoter结合；cidea也促进HDAC从Xdh基因的promoter区解离，从而促进XOR的expression。此外发现，cidec-Fsp27在脂肪细胞核中interacts with C/EBPb to regulate C/EBPb 部分下游基因的表达。