2012年9月21日 電 /生物谷BIOON/ --伊利諾伊州分子和生理學(xué)教授Jongsook Kim Kemper和她的同事們證實(shí)靶向作用于一種微小RNA能夠扭轉(zhuǎn)肥胖小鼠的一些相關(guān)代謝問題,。
科學(xué)家發(fā)現(xiàn)了一種在體內(nèi)能導(dǎo)致脂肪肝疾病、II型糖尿病和其他與肥胖有關(guān)的代謝異常疾病的關(guān)鍵分子,。通過阻斷這種分子,，研究人員就能夠扭轉(zhuǎn)該分子造成的肥胖小鼠的一些病理特征,。
他們的研究結(jié)果刊登在最新一期的PNAS雜志上,。MiR-34A是一種微小RNA,，在肥胖動(dòng)物的肝臟,、脂肪肝疾病人患者中處于高水平,。在這項(xiàng)新研究中,，研究人員發(fā)現(xiàn)miR-34a阻斷beta-Klotho蛋白質(zhì)受體的生成，而beta-Klotho對(duì)肝臟代謝信號(hào)的傳送至關(guān)重要,，beta-Klotho蛋白質(zhì)受體生成被抑制后會(huì)阻礙正常的葡萄糖攝取,、糖原和蛋白質(zhì)合成及其他代謝活動(dòng)。
伊利諾伊大學(xué)分子和生理學(xué)教授Jongsook Kim Kemper說：飯后,，beta-Klotho響應(yīng)來(lái)自小腸的信號(hào)促進(jìn)肝功能運(yùn)作正常,。但是，在肥胖環(huán)境下,，miR-34a的水平遠(yuǎn)遠(yuǎn)高于正常水平,，從而導(dǎo)致beta-Klotho處于異常低水平。
beta-Klotho處于異常低水平的下游效應(yīng)就是血液中的葡萄糖,、肝臟中的脂肪含量增高,，這一影響是顯著的，最終導(dǎo)致肥胖小鼠的肝組織中脂肪過載,，而正常小鼠肝臟中只有極少量的脂肪,。
研究人員使用反義RNA技術(shù)去中和阻斷肥胖小鼠中的miR-34a，這種治療方法帶來(lái)的功效包括肝臟脂肪的降低,、血液中的葡萄糖水平的改善等,。（生物谷：Bioon.com）
doi:10.1073/pnas.1205951109
PMC:
PMID:
Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho
Ting Fua, Sung-E Choia, Dong-Hyun Kima, Sunmi Seoka, Kelly M. Suino-Powellb, H. Eric Xub, and Jongsook Kim Kempera
MicroRNA-34a (miR-34a) is the most highly elevated hepatic miR in obese mice and is also substantially elevated in patients who have steatosis, but its role in obesity and metabolic dysfunction remains unclear. After a meal, FGF19 is secreted from the ileum; binds to a hepatic membrane receptor complex, FGF19 receptor 4 and coreceptor β-Klotho (βKL); and mediates postprandial responses under physiological conditions, but hepatic responses to FGF19 signaling were shown to be impaired in patients with steatosis. Here, we show an unexpected functional link between aberrantly elevated miR-34a and impaired βKL/FGF19 signaling in obesity. In vitro studies show that miR-34a down-regulates βKL by binding to the 3′ UTR of βKL mRNA. Adenoviral-mediated overexpression of miR-34a in mice decreased hepatic βKL levels, impaired FGF19-activated ERK and glycogen synthase kinase signaling, and altered expression of FGF19 metabolic target genes. Consistent with these results, βKL levels were decreased and hepatic responses to FGF19 were severely impaired in dietary obese mice that have elevated miR-34a. Remarkably, in vivo antisense inhibition of miR-34a in obese mice partially restored βKL levels and improved FGF19 target gene expression and metabolic outcomes, including decreased liver fat. Further, anti–miR-34a treatment in primary hepatocytes of obese mice restored FGF19-activated ERK and glycogen synthase kinase signaling in a βKL-dependent manner. These results indicate that aberrantly elevated miR-34a in obesity attenuates hepatic FGF19 signaling by directly targeting βKL. The miR-34a/βKL/FGF19 axis may present unique therapeutic targets for FGF19-related human diseases, including metabolic disorders and cancer.
