circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling

作     者：Xing-Ya Guo Fang Sun Jian-Neng Chen Yu-Qin Wang Qin Pan Jian-Gao Fan 

作者机构：Department of GastroenterologyXinhua HospitalShanghai Jiaotong University School of MedicineShanghai 200092China Department of HepatologyZhengxing HospitalZhangzhou 363000Fujian ProvinceChina Shanghai Key Laboratory of Children’s Digestion and NutritionShanghai 200092China 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2018年第24卷第3期

页      面：323-337页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：National Key Research and Development Plan‘Precision Medicine Research’,No.2017YFSF090203 National Natural Science Foundation of China,No.81070346,No.81270492,No.81470859,No.81270491 and No.81470840 State Key Development Program for Basic Research of China,No.2012CB517501 100 Talents Program,No.XBR2011007h Program of the Committee of Science and Technology,No.09140903500 

主　　题：hepatocytes steatosis circRNA_0046366 miR-34a peroxisome proliferator-activated receptorα 

摘      要：AIM To investigate micro(mi)R-34 a-antagonizing circular(circ)RNA that underlies hepatocellular *** The effect of circ RNA on mi R-34 a was recognized by the mi RNA response element(MRE), and validated by the dual-luciferase reporter assay. Its association with hepatocellular steatosis was investigated in Hep G2-based hepatocellular steatosis induced by free fatty acids(FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the steatosis-related circRNA by expression vector, analysis of mi R-34 a activity,peroxisome proliferator-activated receptor(PPAR)α level, and expression of downstream genes were carried out so as to reveal its impact on the mi R-34 a/PPARα regulatory system. Both triglyceride(TG) assessment and cytopathological manifestations uncovered the role of circRNA in miR-34 a-dependent *** Bioinformatic and functional analysis verified circRNA_0046366 to antagonize the activity of mi R-34 a via MRE-based complementation. In contrast to its lowered level during FFA-induced hepatocellular steatosis, circ RNA_0046366 up-regulation abolished the mi R-34 a-dependent inhibition of PPARα that played a critical role in metabolic signaling pathways. PPARα restoration exerted transcriptional improvement to multiple genes responsible for lipid metabolism. TGspecific lipolytic genes [carnitine palmitoyltransferase 1 A(CPT1 A) and solute-carrier family 27 A(SLC27 A)] among these showed significant increase in their expression levels. The circ RNA_0046366-related rebalancing of lipid homeostasis led to dramatic reduction of TG content, and resulted in the ameliorated phenotype of hepatocellular *** Dysregulation of circ RNA_0046366/mi R-34 a/PPARα signaling may be a novel epigenetic mechanism underlying hepatocellular steatosis. circ RNA_0046366 serves as a potential target for the treatment of hepatic steatosis.