Lan Xi, Ren Jiajun, Du Xiaojuan, Zhang Lin, Wang Shuaishuai, Yang Xudong, Lu Shemin
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Beijing, China.
Xi'an Fengcheng Hospital, Xi'an, Shaanxi, 710061, China.
Mol Cell Endocrinol. 2023 Dec 1;578:112061. doi: 10.1016/j.mce.2023.112061. Epub 2023 Sep 5.
Hepatic lipid deposition is the main cause of non-alcoholic fatty liver disease (NAFLD). Our previous study identified that lnc-HC prevents NAFLD by increasing the expression of miR-130b-3p. In the present study, we show that lnc-HC, an lncRNA derived from hepatocytes, positively controls miR-130b-3p maturation at multiple levels and contributes to its action by enhancing the assembly of an RNA-induced silencing complex (RISC). lnc-HC negatively regulates the downstream target genes of miR-130b-3p, including peroxisome proliferator-activated receptor gamma (PPARγ) and acyl-CoA synthetase long-chain family member 1 and 4 (Acsl1 and Acsl4, respectively), thus suppressing hepatic lipid droplet accumulation. Mechanistically, lnc-HC enhanced the promoter activity of miR-130b-3p by positively regulating the expression of transcription factors MAF bZIP transcription factor B (Mafb) and Jun proto-oncogene (Jun). Then, lnc-HC contributed the processing step of primary (pri-) miR-130b and strengthened the interaction between Drosha enzyme and the 5'-flanking sequence of pri-miR-130b to produce more precursor transcripts. Through direct binding with the chaperone heat shock protein 90 alpha family class A member 1 (HSP90AA1), lnc-HC contributed to RISC assembly, which was composed of HSP90AA1, argonaute RISC catalytic component 2 (AGO2) and miR-130b-3p. In a high-fat, high-cholesterol-induced hepatic lipid disorder E3 model, we confirmed that the hepatic expression of lnc-HC/miR-130b-3p negatively correlated with that of the target genes and was closely associated with liver triglycerides concentration. These findings provide a deeper understanding of the regulatory roles of lnc-HC in hepatic lipid metabolism and NAFLD development.
肝脏脂质沉积是非酒精性脂肪性肝病（NAFLD）的主要病因。我们之前的研究发现lnc-HC通过增加miR-130b-3p的表达来预防NAFLD。在本研究中，我们发现lnc-HC是一种源自肝细胞的lncRNA，它在多个水平上正向调控miR-130b-3p的成熟，并通过增强RNA诱导沉默复合体（RISC）的组装来促进其作用。lnc-HC负向调控miR-130b-3p的下游靶基因，包括过氧化物酶体增殖物激活受体γ（PPARγ）以及酰基辅酶A合成酶长链家族成员1和4（分别为Acsl1和Acsl4），从而抑制肝脏脂质滴的积累。机制上，lnc-HC通过正向调控转录因子MAF bZIP转录因子B（Mafb）和原癌基因Jun（Jun）的表达来增强miR-130b-3p的启动子活性。然后，lnc-HC促进初级（pri-）miR-130b的加工步骤，并加强Drosha酶与pri-miR-130b的5'侧翼序列之间的相互作用，以产生更多的前体转录本。通过与伴侣热休克蛋白90α家族A类成员1（HSP90AA1）直接结合，lnc-HC促进了由HSP90AA1、AGO2和miR-130b-3p组成的RISC组装。在高脂、高胆固醇诱导的肝脏脂质紊乱E3模型中，我们证实lnc-HC/miR-130b-3p的肝脏表达与靶基因的表达呈负相关，且与肝脏甘油三酯浓度密切相关。这些发现为深入理解lnc-HC在肝脏脂质代谢和NAFLD发展中的调控作用提供了依据。
