Mechanisms Underlying the Pathogenesis of Non-alcoholic Fatty Liver Disease

 描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是全球主要的健康问题之一。然而，人们对潜在的机制知之甚少。微小RNA（miRNA）是小的（19-22个核苷酸）非编码RNA分子，其结合至mRNA的3'非翻译区（3'-UTR）以转录后调节基因表达，通常导致基因表达的抑制。最近的研究表明，miRNAs在调节糖脂代谢以及其他生物学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 β（HNF 4 β）是核激素受体超家族成员，在维持胆汁酸、脂质和葡萄糖的稳态中发挥重要作用。虽然已知肝HNF 4 β的丢失会导致肝脂肪变性，但HNF 4 β在NAFLD进展中的作用之前尚未研究。我们的初步数据显示，1）非酒精性脂肪性肝炎（NASH）患者的miR-34 a和miR-149表达显著增加，HNF 4 β表达显著降低，2）糖尿病小鼠或高脂饮食（HFD）喂养小鼠的肝脏miR-34 a和miR-149表达也增加，HNF 4 β表达显著降低，和3）肝miR-34 a或miR-149的过表达导致肝HNF 4 β表达的减少和肝甘油三酯（TG）水平的增加。基于这些初步数据，我们假设在响应特定的代谢线索时，涉及miR-34 a、miR-149和HNF 4 β的级联反应被激活以增加肝脏TG水平，从而促进NAFLD的发展和进展。为了验证这一假设，我们将利用功能获得和功能丧失的方法来进一步表征miR-34 a、miR-149和HNF 4受体在肝脏TG代谢和NAFLD的发展和进展中的作用。实现本申请中提出的具体目标将为NAFLD发病机制提供新的和重要的见解，并可能导致识别用于治疗NAFLD的新靶标。

 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.