circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis.
circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis.
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circRNA_0046367 预防脂质过氧化的肝毒性：对肝脂肪变性的抑制作用
DOI：
10.1155/2017/3960197
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发表时间：
2017
影响因子：
--
通讯作者：
Fan JG
中科院分区：
文献类型：
--
作者：
Guo XY;Chen JN;Sun F;Wang YQ;Pan Q;Fan JG
肝脏脂肪变性反映了与甘油三酯积累和脂质过氧化相关的miRNA相关的病理学紊乱，其导致非酒精性脂肪性肝炎、肝纤维化/肝硬化，甚至肝细胞癌。环状RNA（circRNA）/miRNA相互作用揭示了一个新的表观遗传调控层，但在肝脂肪变性中以miRNA为靶点的circRNA仍不确定。在这里，我们发现circRNA_0046367是miR-34 a的内源性调节剂，是肝脂肪变性的基础。与其在体内和体外肝细胞脂肪变性期间的表达丧失相反，circRNA_0046367正常化通过阻断miRNA/mRNA与miRNA反应元件（MRE）的相互作用来消除miR-34 a对过氧化物酶体增殖物激活受体α（PPARα）的抑制作用。PPARα恢复导致与脂质代谢相关的基因的转录激活，包括肉毒碱棕榈酰转移酶2（CPT 2）和酰基辅酶A结合结构域3（ACBD 3），从而导致脂肪变性消退。脂肪变性相关脂质过氧化的肝毒性，其特征在于线粒体功能障碍、生长停滞和细胞凋亡，因此在circRNA_0046367给药后得到预防。这些发现表明circRNA_0046367/miR-34 a/PPARα调节系统是肝脂肪变性的基础。circRNA_0046367的正常表达可以在脂肪变性减弱的基础上改善脂肪氧化应激。因此，circRNA_0046367被认为是治疗脂质过氧化损伤的潜在途径。
Hepatic steatosis reflects the miRNA-related pathological disorder with triglyceride accumulation and lipid peroxidation, which leads to nonalcoholic steatohepatitis, liver fibrosis/cirrhosis, and even hepatocellular carcinoma. Circular RNA (circRNA)/miRNA interaction reveals a novel layer of epigenetic regulation, yet the miRNA-targeting circRNA remains uncertain in hepatic steatosis. Here, we uncover circRNA_0046367 to be endogenous modulator of miR-34a that underlies hepatic steatosis. In contrast to its expression loss during the hepatocellular steatosis in vivo and in vitro, circRNA_0046367 normalization abolished miR-34a's inhibitory effect on peroxisome proliferator-activated receptor α (PPARα) via blocking the miRNA/mRNA interaction with miRNA response elements (MREs). PPARα restoration led to the transcriptional activation of genes associated with lipid metabolism, including carnitine palmitoyltransferase 2 (CPT2) and acyl-CoA binding domain containing 3 (ACBD3), and then resulted in the steatosis resolution. Hepatotoxicity of steatosis-related lipid peroxidation, being characterized by mitochondrial dysfunction, growth arrest, and apoptosis, is resultantly prevented after the circRNA_0046367 administration. These findings indicate a circRNA_0046367/miR-34a/PPARα regulatory system underlying hepatic steatosis. Normalized expression of circRNA_0046367 may ameliorate the lipoxidative stress on the basis of steatosis attenuation. circRNA_0046367, therefore, is suggested to be potential approach to the therapy of lipid peroxidative damage.
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影响因子：
13.5
作者：
Birkenfeld, Andreas L.;Shulman, Gerald I.
通讯作者：
Shulman, Gerald I.
影响因子：
14.9
作者：
Griffiths-Jones S;Grocock RJ;van Dongen S;Bateman A;Enright AJ
通讯作者：
Enright AJ
影响因子：
--
作者：
Ahmed, Ikhlak;Karedath, Thasni;Malek, Joel A.
通讯作者：
Malek, Joel A.
影响因子：
25.7
作者：
Castro, Rui E.;Ferreira, Duarte M. S.;Rodrigues, Cecilia M. P.
通讯作者：
Rodrigues, Cecilia M. P.
DOI：
10.1111/j.1440-1746.2007.05002.x
发表时间：
2007-06-01
影响因子：
4.1
作者：
Farrell, Geoffrey C.;Chitturi, Shivakumar;Sollano, Jose D.
通讯作者：
Sollano, Jose D.