The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling.
The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling.
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DOI：
10.1186/1471-2164-14-575
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发表时间：
2013-08-28
期刊：
影响因子：
4.4
通讯作者：
Wan YJ
中科院分区：
文献类型：
--
作者：
He Y;Gong L;Fang Y;Zhan Q;Liu HX;Lu Y;Guo GL;Lehman-McKeeman L;Fang J;Wan YJ
眼睛和皮肤是明显的类维生素A靶器官。维生素A缺乏会导致夜盲症，类维生素A被广泛用于治疗痤疮和牛皮癣。然而，超过90%的身体总视黄醇储存在肝星状细胞中。此外，肝细胞产生最大量的视黄醇结合蛋白和细胞视黄酸结合蛋白，以分别从肝储存池中动员视黄醇并将视黄醇递送至其受体。此外，在所有细胞类型中，肝细胞表达最高量的维甲酸x受体α（RXRα）。令人惊讶的是，内源性类维生素A在肝脏中的功能很少受到关注。基于染色质免疫沉淀和测序产生的数据，已经确定了转录因子的整体DNA结合，包括类维生素A X受体α（RXRα）沿着其配偶体，即视黄酸受体α（RARα）、维生素A X受体（PXR）、肝X受体（LXR）、法尼醇X受体（FXR）和过氧化物酶体增殖物激活受体α（PPARα）。基于结合，功能注释阐明了这些受体在调节肝脏脂质稳态中的作用。为了将DNA结合数据与基因表达数据相关联，在接受和不接受RA治疗的野生型和肝脏RXRα缺失小鼠中研究了576个调节脂质稳态的基因的表达模式。结果表明，RA治疗和RXRα缺乏在调节脂质稳态方面具有相反的作用。选择可清楚区分配体处理和受体缺陷的影响的基因子集（114）用于进一步的功能分析。表达数据表明，RA处理可以产生不饱和脂肪酸，并诱导甘油三酯分解，胆汁酸分泌，脂解和类维生素A消除。相反，RXRα缺乏可诱导饱和脂肪酸、甘油三酯、胆固醇、胆汁酸和类维生素A的合成。此外，DNA结合数据表明RARα、PXR、LXR、FXR和PPARα在调节RA/RXRα依赖性基因表达水平方面存在广泛的相互作用。此外，RA降低小鼠血清胆固醇、甘油三酯和胆汁酸水平。我们首次描述了肝脏类风湿关节炎的作用。肝脏RA通过RXRα及其伴侣介导调节脂质稳态。
The eyes and skin are obvious retinoid target organs. Vitamin A deficiency causes night blindness and retinoids are widely used to treat acne and psoriasis. However, more than 90% of total body retinol is stored in liver stellate cells. In addition, hepatocytes produce the largest amount of retinol binding protein and cellular retinoic acid binding protein to mobilize retinol from the hepatic storage pool and deliver retinol to its receptors, respectively. Furthermore, hepatocytes express the highest amount of retinoid x receptor alpha (RXRα) among all the cell types. Surprisingly, the function of endogenous retinoids in the liver has received very little attention. Based on the data generated from chromatin immunoprecipitation followed by sequencing, the global DNA binding of transcription factors including retinoid x receptor α (RXRα) along with its partners i.e. retinoic acid receptor α (RARα), pregnane x receptor (PXR), liver x receptor (LXR), farnesoid x receptor (FXR), and peroxisome proliferator-activated receptor α (PPARα) has been established. Based on the binding, functional annotation illustrated the role of those receptors in regulating hepatic lipid homeostasis. To correlate the DNA binding data with gene expression data, the expression patterns of 576 genes that regulate lipid homeostasis were studied in wild type and liver RXRα-null mice treated with and without RA. The data showed that RA treatment and RXRα-deficiency had opposite effects in regulating lipid homeostasis. A subset of genes (114), which could clearly differentiate the effect of ligand treatment and receptor deficiency, were selected for further functional analysis. The expression data suggested that RA treatment could produce unsaturated fatty acids and induce triglyceride breakdown, bile acid secretion, lipolysis, and retinoids elimination. In contrast, RXRα deficiency might induce the synthesis of saturated fatty acids, triglyceride, cholesterol, bile acids, and retinoids. In addition, DNA binding data indicated extensive cross-talk among RARα, PXR, LXR, FXR, and PPARα in regulating those RA/RXRα-dependent gene expression levels. Moreover, RA reduced serum cholesterol, triglyceride, and bile acid levels in mice. We have characterized the role of hepatic RA for the first time. Hepatic RA mediated through RXRα and its partners regulates lipid homeostasis.
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影响因子：
14.9
作者：
Cui JY;Gunewardena SS;Rockwell CE;Klaassen CD
通讯作者：
Klaassen CD
影响因子：
3.9
作者：
Theken, Katherine N.;Deng, Yangmei;Lee, Craig R.
通讯作者：
Lee, Craig R.
影响因子：
3
作者：
Salmon-Divon M;Dvinge H;Tammoja K;Bertone P
通讯作者：
Bertone P
影响因子：
5.8
作者：
Chen, Shiyong;Wang, Kun;Wan, Yu-Jui Yvonne
通讯作者：
Wan, Yu-Jui Yvonne
DOI：
10.1002/hep.23450
发表时间：
2010-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Thomas AM;Hart SN;Kong B;Fang J;Zhong XB;Guo GL
通讯作者：
Guo GL