miR-30c在炎症导致的肝脏脂肪沉积中的作用及机制研究

Non-alcoholic fatty liver disease (NAFLD) is defined as excessive accumulation of lipid not due to excess alcohol consumption. Hepatic fat accumulation is considered as the basis of NAFLD. During our previous study, we have found that chronic low-grade inflammation induced hepatic fat accumulation, but much of its pathogenesis remains unclear. miRNAs are endogenous 22 nucleotide RNAs which can bind to the sequences localized in the 3'-untranslated regions of their target mRNAs and destabilize mRNAs or inhibit mRNAs translation. More recently, miRNAs have been highlighted as potential regulation points of hepatic fat accumulation induced by inflammation. miRNAs play important roles in the regulation of many biological pathways and have strong associations with inflammation and hepatic lipid metabolisms. The expression of miRNAs in the liver of inflammatory mice models were detected by miRNA array in our previous work. Statistical upregulation of miR-30c were found and the results were verified by RT-PCR. Several miR-30c target genes predicted by targetscan 6.0 were found to relate to lipid metabolisms. Thus we hypothesized that chronic low-grade inflammation induced hepatic fat accumulation by up-regulating the expression of miR-30c in the liver and interacting with its target genes related to lipid metabolism. This study will help to clarify the role of miR-30c in the hepatic lipid metabolisms and the mechanisms of hepatic fat accumulation induced by chronic low-grade inflammation.

非酒精性脂肪肝（Non-alcoholic fatty liver disease，NAFLD）是指由非酗酒原因造成的大量脂肪沉积于肝脏。肝脏脂肪沉积是NAFLD发生发展的基础。我们的前期工作观察到慢性低度炎症（简称炎症）促进小鼠肝脏脂肪沉积，但机制未明。miRNA是内源性的非编码RNA，常通过抑制靶基因的表达广泛参与各种生命活动，其与炎症及肝脏脂代谢关系密切，是炎症导致的肝脏脂肪沉积的潜在调控点。我们运用miRNA基因芯片及RT-PCR证实炎症小鼠肝脏miR-30c表达明显上调，并运用Targetscan6.0 成功预测出其脂代谢相关靶基因。本研究在前期工作基础上提出：炎症通过上调肝脏miR-30c，并作用于脂代谢相关靶基因，导致肝脏脂代谢障碍，促进肝脏脂肪沉积这一假说。有助于阐明miR-30c在肝脏脂代谢的调控及炎症促进肝脏脂肪沉积中的作用及机制。

炎症是代谢相关性疾病的核心，本研究最初目的是拟探讨microRNAs在炎症导致的肝脏脂质沉积中的作用，研究过程中我们发现，作为体内主要的内分泌组织之一，脂肪组织在代谢紊乱过程中也具有重要地位，且脂肪组织炎症是多种代谢相关性疾病的中心环节。近年来有研究显示脂肪组织中microRNAs的表达失调与肥胖相关代谢性疾病密切相关，然而其是否参与调节脂肪细胞炎症还知之甚少。本研究发现，高脂饮食诱导的肥胖小鼠体内脂肪组织处于显著的炎症状态，同时 miR-1934的表达显著降低；同时，在TNFα干预前3T3-L1和成熟3T3-L1脂肪细胞模拟的炎症状态中，miR-1934的表达亦显著降低；进一步在上述炎症细胞模型中过表达miR-1934，能明显降低炎症细胞模型中IL-6、MCP-1等炎症因子的水平，提示miR-1934能有效改善脂肪细胞中的炎症状态。本研究有助于进一步阐明肥胖相关脂肪组织炎症中的相关机制。