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非编码RNA调节元件促进小鼠体内苯丙氨酸的代谢
作者:小柯机器人 发布时间:2021/8/8 13:03:22

美国德克萨斯大学安德森癌症中心的杨柳青、Chunru Lin和Shuxing Zhang研究团队合作的研究发现非编码RNA调控元件增强小鼠体内苯丙氨酸代谢。相关论文于2021年8月6日发表于国际学术期刊《科学》杂志。

研究人员证明了小鼠长非编码RNA (lncRNA) Pair和人lncRNA HULC与苯丙氨酸羟化酶(PAH)相关。Pair敲除小鼠表现出过多的血苯丙氨酸 (Phe)、霉味、色素减退、生长迟缓以及进行性神经系统症状,包括癫痫发作,而这些症状与人苯丙酮尿症 (PKU)类似。HULC 耗竭导致人诱导多能干细胞分化肝细胞中PAH的酶活性降低。

从机制上讲,HULC通过促进多环芳烃-底物和多环芳烃-辅因子相互作用来调节多环芳烃的酶活性。为了探究恢复肝脏 lncRNA是否具有治疗可行性,研究人员设计了具有肝脏富集功能GalNAc标记的lncRNA类似物。用GalNAc-HULC类似物处理降低了Pair-/-和PahR408W/R408W小鼠中过多的 Phe,并提高了小鼠对Phe的耐受性。

据介绍,尚不清楚lncRNA在遗传性代谢疾病中的功能,如PKU。

附:英文原文

Title: A noncoding RNA modulator potentiates phenylalanine metabolism in mice

Author: Yajuan Li, Zhi Tan, Yaohua Zhang, Zhao Zhang, Qingsong Hu, Ke Liang, Yao Jun, Youqiong Ye, Yi-Chuan Li, Chunlai Li, Lan Liao, Jianming Xu, Zhen Xing, Yinghong Pan, Sujash S. Chatterjee, Tina K. Nguyen, Heidi Hsiao, Sergey D. Egranov, Nagireddy Putluri, Cristian Coarfa, David H. Hawke, Preethi H. Gunaratne, Kuang-Lei Tsai, Leng Han, Mien-Chie Hung, George A. Calin, Fares Namour, Jean-Louis Guéant, Ania C. Muntau, Nenad Blau, V. Reid Sutton, Manuel Schiff, Franois Feillet, Shuxing Zhang, Chunru Lin, Liuqing Yang

Issue&Volume: 2021/08/06

Abstract: The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell–differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair/ and PahR408W/R408W mice and improved the Phe tolerance of these mice.

DOI: 10.1126/science.aba4991

Source: https://science.sciencemag.org/content/373/6555/662

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037