Mechanisms Underlying the Pathogenesis of Non-alcoholic Fatty Liver Disease

 描述(由申请者提供)：非酒精性脂肪性肝病(NAFLD)是全球主要的健康问题之一。然而，人们对其背后的机制知之甚少。MicroRNAs(MiRNAs)是一种小的(19-22个核苷酸)非编码RNA分子，它与mRNAs的3‘非翻译区(3’-UTR)结合，在转录后调节基因表达，通常导致基因表达抑制。最近的数据表明，miRNAs在调节脂肪和葡萄糖代谢以及许多其他生物过程中发挥着重要作用。核激素受体是配体激活的转录因子，调节发育和成人生理。肝细胞核因子4(HNF4)是核激素受体超家族的一员，在维持胆汁酸、血脂和血糖的动态平衡中起着重要作用。尽管肝脏HNF4缺失已知会导致肝脏脂肪变性，但HNF4在非酒精性脂肪肝进展过程中的作用尚未被研究过。我们的初步数据显示，1)非酒精性脂肪性肝炎(NASH)患者肝脏miR-34a和miR-149的表达显著增加，而hNF4的表达显著降低；2)糖尿病小鼠和高脂饮食小鼠的肝脏miR-34a和miR-149的表达也显著增加，肝脏hNF4的表达显著降低；3)肝脏miR-34a或miR-149的过度表达导致肝脏hNF4的表达降低和肝脏甘油三酯(TG)水平的升高。基于这些初步数据，我们推测，在特定的代谢线索(S)的响应下，涉及miR-34a、miR-149和HNF4的级联被激活，从而提高了肝脏TG水平，从而促进了非酒精性脂肪肝的发生发展。为了验证这一假说，我们将利用功能获得和功能丧失的方法来进一步研究miR-34a、miR-149和HNF4在肝脏甘油三酯代谢和非酒精性脂肪肝的发生发展中的作用。实现本申请中提出的特定目的将为研究非酒精性脂肪肝的发病机制提供新的重要见解，并可能导致寻找治疗非酒精性脂肪肝的新靶点(S)。

 DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. However, the underlying mechanism has been poorly understood. MicroRNAs (miRNAs) are small (19-22 nucleotide) noncoding RNA molecules that bind to the 3' untranslated region (3'-UTR) of mRNAs to post- transcriptionally regulate gene expression, usually leading to inhibition of gene expression. Recent data have demonstrated that miRNAs play an important role in regulating lipid and glucose metabolism as well as many other biological processes. Nuclear hormone receptors are ligand-activated transcription factors that regulate both development and adult physiology. Hepatocyte nuclear factor 4 (HNF4) is a member of the nuclear hormone receptor superfamily and has been shown to play a critical role in maintaining bile acid, lipid and glucose homeostasis. Although loss of hepatic HNF4 is known to cause liver steatosis, the role of HNF4 in the progression of NAFLD has not been investigated before. Our preliminary data have shown that 1) patients with non-alcoholic steatohepatitis (NASH) have a significant increase in miR-34a and miR-149 expression and a marked decrease in HNF4 expression, 2) diabetic mice or high fat diet (HFD)-fed mice also have increased hepatic miR-34a and miR-149 expression and a significant reduction in hepatic HNF4 expression, and 3) over-expression of hepatic miR-34a or miR-149 causes a reduction in hepatic HNF4 expression and an increase in hepatic triglyceride (TG) levels. Based on these preliminary data, we hypothesize that in response to specific metabolic cue(s), a cascade involving miR-34a, miR-149 and HNF4 is activated to increase hepatic TG levels, therefore facilitating the development and progression of NAFLD. To test this hypothesis, we will utilize both gain- and loss-of-function approaches to further characterize the role of miR-34a, miR-149 and HNF4in hepatic TG metabolism and the development and progression of NAFLD. Accomplishing the specific aims proposed in this application will provide novel and important insights into the mechanism underlying the pathogenesis of NAFLD, and may lead to identification of novel target(s) for treatment of NAFLD.