Long Noncoding RNA lnc-HC Regulates PPARγ-Mediated Hepatic Lipid Metabolism through miR-130b-3p
Long Noncoding RNA lnc-HC Regulates PPARγ-Mediated Hepatic Lipid Metabolism through miR-130b-3p
复制标题
长非编码 RNA lnc-HC 通过 miR-130b-3p 调节 PPAR gamma 介导的肝脂质代谢
DOI：
10.1016/j.omtn.2019.10.018
复制
发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Lu, Shemin
中科院分区：
文献类型：
--
作者：
Lan, Xi;Wu, Litao;Lu, Shemin
非酒精性脂肪性肝病（NAFLD）是由于肝细胞内过度的脂质积累引起的。代谢核受体（MNRs）在脂质稳态中起着重要作用。我们已经发现了一种新的长链非编码RNA (lncRNA), lnc-HC，它通过降低Cyp7a1和Abca1的表达来调节肝细胞胆固醇代谢。在这里，我们通过一种新的lncRNA调控机制进一步阐明了它在肝脂肪酸和甘油三酯（TG）代谢中的作用。在体外研究中，lnc-HC最突出的靶点是PPAR γ。进一步研究发现，lnc-HC在mRNA和蛋白水平上负调控PPAR γ，抑制肝细胞脂滴的形成。重要的是，lnc-HC调节PPAR γ表达的功能依赖于从转录到转录后水平调节miR-130b-3p的表达，而不是通过lncRNA的关键调节模式。在体内，lnc-HC表达降低可显著降低miR-130b-3p表达，诱导PPAR γ表达，升高高脂血症大鼠肝脏中TG浓度。这些发现有助于进一步了解lnc-HC在肝脏脂质代谢中的调节模式，并可能为改善脂质稳态提供可能的治疗靶点。
Nonalcoholic fatty liver disease (NAFLD) is due to the excessive lipid accumulation within hepatocytes. Metabolic nuclear receptors (MNRs) play great roles in lipid homeostasis. We have identified a novel long noncoding RNA (lncRNA), lnc-HC, which regulates hepatocytic cholesterol metabolism through reducing Cyp7a1 and Abca1 expression. Here, we further elucidate its roles in hepatic fatty acid and triglyceride (TG) metabolism through a novel lncRNA regulatory mechanism. The most prominent target of lnc-HC identified by in vitro study is PPAR gamma. Further studies revealed that lnc-HC negatively regulates PPAR gamma at both the mRNA and protein levels and suppresses hepatocytic lipid droplet formation. Importantly, the function of lnc-HC in regulating PPAR gamma expression depends on modulating miR-130b-3p expression from the transcriptional to the post-transcriptional level, not through lncRNA's critical modulating patterns. In vivo, the reduction of lnc-HC expression significantly decreases miR-130b-3p expression, induces PPAR gamma expression, and increases TG concentration in rat livers with hyperlipidemia. These findings further help in understanding the regulatory pattern of lnc-HC in hepatic lipid metabolism and might present a possible therapeutic target for improving lipid homeostasis.