2012年9月21日 电 /生物谷BIOON/ --伊利诺伊州分子和生理学教授Jongsook Kim Kemper和她的同事们证实靶向作用于一种微小RNA能够扭转肥胖小鼠的一些相关代谢问题。
科学家发现了一种在体内能导致脂肪肝疾病、II型糖尿病和其他与肥胖有关的代谢异常疾病的关键分子。通过阻断这种分子，研究人员就能够扭转该分子造成的肥胖小鼠的一些病理特征。
他们的研究结果刊登在最新一期的PNAS杂志上。MiR-34A是一种微小RNA，在肥胖动物的肝脏、脂肪肝疾病人患者中处于高水平。在这项新研究中，研究人员发现miR-34a阻断beta-Klotho蛋白质受体的生成，而beta-Klotho对肝脏代谢信号的传送至关重要，beta-Klotho蛋白质受体生成被抑制后会阻碍正常的葡萄糖摄取、糖原和蛋白质合成及其他代谢活动。
伊利诺伊大学分子和生理学教授Jongsook Kim Kemper说：饭后，beta-Klotho响应来自小肠的信号促进肝功能运作正常。但是，在肥胖环境下，miR-34a的水平远远高于正常水平，从而导致beta-Klotho处于异常低水平。
beta-Klotho处于异常低水平的下游效应就是血液中的葡萄糖、肝脏中的脂肪含量增高，这一影响是显著的，最终导致肥胖小鼠的肝组织中脂肪过载，而正常小鼠肝脏中只有极少量的脂肪。
研究人员使用反义RNA技术去中和阻断肥胖小鼠中的miR-34a，这种治疗方法带来的功效包括肝脏脂肪的降低、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.
