Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1.
Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1.
复制标题
DOI：
10.1053/j.gastro.2012.01.007
复制
发表时间：
2012-05
期刊：
影响因子：
29.4
通讯作者：
Kim SG
中科院分区：
文献类型：
--
作者：
Lee CG;Kim YW;Kim EH;Meng Z;Huang W;Hwang SJ;Kim SG
肝纤维化过程中会发生肝细胞损伤。 MicroRNA (miRNA) 调节其中一些过程，其中一些由法尼醇 X 受体 (FXR) 调节。我们使用来自患者的纤维化肝组织和肝细胞研究了 FXR 抑制特定 miRNA 在肝细胞损伤中的作用。我们使用免疫组织化学或实时聚合酶链反应来分析人和小鼠肝脏样本中的蛋白质和 miRNA。 HepG2 细胞用 pre-miRNA、反义寡核苷酸、小干扰 RNA、肝激酶 B1 (LKB1) (STK11) 的 3' 非翻译区或过表达构建体转染并进行分析。与轻度疾病患者的样本相比，重度纤维化患者的肝组织中 FXR 水平较低，肝细胞死亡量较多。当肝脏中 FXR 表达受到破坏时，几种 miRNA 的水平发生变化；其中之一，miR-199a-3p，在严重纤维化患者中显着上调。 FXR 的配体激活可降低 HepG2 细胞中 miR-199a-3p 的水平。 LKB1 信使 RNA 被确定为 miR-199a-3p 的靶标，其表达在人纤维化肝组织中降低。 FXR 过度表达或培养的肝细胞与 FXR 配体一起孵育会上调 LKB1；转染 miR-199a-3p 的细胞中未诱导 LKB1。将 HepG2 细胞与 FXR 配体一起孵育，或将配体注射到小鼠体内，可保护肝细胞免受损伤并增加 LKB1 水平；与未与 FXR 配体一起孵育的细胞相比，miR-199a-3p 的水平降低。 FXR 的激活减少了线粒体功能障碍和氧化应激，并增加了肝细胞的存活率。在肝细胞中，FXR 抑制 miR-199a-3p 的产生。在人类和小鼠的纤维化肝脏中，FXR 表达减少，miR-199a-3p 水平增加，从而降低 LKB1 水平。因此，FXR 通过抑制 miR-199a-3p 从而增加 LKB1 的水平来保护肝细胞免受损伤。
Hepatocyte injury occurs during liver fibrogenesis. MicroRNAs (miRNA) regulate some of these processes, and some are regulated by the farnesoid X receptor (FXR). We investigated the effect of repression of specific miRNAs by FXR in hepatocyte injury using fibrotic liver tissue from patients and hepatocytes. We used immunohistochemistry or real-time polymerase chain reaction to analyze proteins and miRNAs in human and mouse liver samples. HepG2 cells were transfected with pre-miRNA, antisense oligonucleotides, small interfering RNAs, the 3′-untranslated region of liver kinase B1 (LKB1) (STK11), or constructs for overexpression, and analyzed. Liver tissue from patients with severe fibrosis had lower levels of FXR and greater amounts of hepatocyte death than samples from patients with mild disease. Levels of several miRNAs changed when FXR expression was disrupted in the liver; one of these, miR-199a-3p, was significantly up-regulated in patients with severe fibrosis. Activation of FXR by its ligand reduced the level of miR-199a-3p in HepG2 cells. LKB1 messenger RNA was identified as a target of miR-199a-3p, and its expression was reduced in human fibrotic liver tissue. Overexpression of FXR or incubation of cultured hepatocytes with the FXR ligand up-regulated LKB1; LKB1 was not induced in cells transfected with miR-199a-3p. Incubation of HepG2 cells with FXR ligand, or injection of the ligand into mice, protected hepatocytes from injury and increased levels of LKB1; levels of miR-199a-3p were reduced compared with cells that were not incubated with the FXR ligand. Activation of FXR reduced mitochondrial dysfunction and oxidative stress and increased hepatocyte survival. In hepatocytes, FXR represses production of miR-199a-3p. In fibrotic livers of humans and mice, FXR expression is reduced, increasing levels of miR-199a-3p, which reduces levels of LKB1. FXR therefore protects hepatocytes from injury by repressing miR-199a-3p and thereby increasing levels of LKB1.
登录
查看更多内容
影响因子：
5
作者：
Marquez, Rebecca T.;Bandyopadhyay, Sarmistha;McCaffrey, Anton P.
通讯作者：
McCaffrey, Anton P.
影响因子：
11.4
作者：
Boudeau, J;Baas, AF;Alessi, DR
通讯作者：
Alessi, DR
DOI：
10.1073/pnas.96.17.9671
发表时间：
1999-08-17
影响因子：
11.1
作者：
Marconcini, L;Marchio, S;Oliviero, S
通讯作者：
Oliviero, S
影响因子：
13.5
作者：
Roderburg, Christoph;Urban, Gerd-Willem;Luedde, Tom
通讯作者：
Luedde, Tom
DOI：
10.1111/j.1742-4658.2010.07632.x
发表时间：
2010-05
期刊：
The FEBS journal
影响因子：
--
作者：
Jiang X;Tsitsiou E;Herrick SE;Lindsay MA
通讯作者：
Lindsay MA