Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver.
Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver.
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转录组关联分析将miR-375鉴定为人肝脏可变的对乙酰氨基葡萄糖醛酸化的主要决定因素。
DOI：
10.1016/j.bcp.2016.08.014
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发表时间：
2016-10-01
影响因子：
5.8
通讯作者：
Court, Michael H.
中科院分区：
文献类型：
--
作者：
Papageorgiou, Loannis;Freytsis, Marina;Court, Michael H.
关键词：
对乙酰氨基酚是包括美国在内的许多国家急性肝衰竭（ALF）的主要原因。UDP-葡萄糖醛酸基转移酶（UGT）1A亚家族酶的肝脏葡萄糖醛酸化是对乙酰氨基酚消除的主要途径。葡萄糖醛酸化减少可能使某些个体易患对乙酰氨基酚诱导的ALF，但葡萄糖醛酸化减少的潜在机制尚不清楚。我们假设特定的microRNA（miRNAs）可能通过直接作用于所有UGT 1A酶转录本共有的UGT 1A 3 '-UTR，或间接作用于调节UGT 1A表达的转录因子，从而降低UGT 1A活性。我们使用已知对乙酰氨基酚葡萄糖醛酸化活性的人类肝脏库进行了无偏倚的miRNA全转录组关联分析。在评估的754种miRNA中，与具有高活性的那些相比，在具有低对乙酰氨基酚葡萄糖醛酸化活性的肝脏中鉴定出9种miRNA显著过表达（p<0.05; >2倍）。miR-375显示出最高的差异（>10倍），并被选择用于进一步的机制验证。我们使用计算机分析和荧光素酶报告基因测定证明，miR-375在芳烃受体（AhR）基因的3 '-UTR中具有独特的功能结合位点。此外，miR-375在LS 180细胞中的过表达表明，内源性AhR蛋白（40%）和mRNA（10%）以及AhR调节酶（包括UGT 1A 1、UGT 1A 6和CYP 1A 2）的酶活性和/或mRNA受到显著抑制，而不影响不受AhR调节的UGT 2B 7。因此，miR-375被鉴定为UGT 1A介导的肝脏对乙酰氨基酚葡萄糖醛酸化的新型阻遏物，其通过减少AhR表达，这可能使一些个体易患对乙酰氨基酚诱导的ALF的风险增加。
Acetaminophen is the leading cause of acute liver failure (ALF) in many countries including the United States. Hepatic glucuronidation by UDP-glucuronosyltransferase (UGT) 1A subfamily enzymes is the major route of acetaminophen elimination. Reduced glucuronidation may predispose some individuals to acetaminophen-induced ALF, but mechanisms underlying reduced glucuronidation are poorly understood. We hypothesized that specific microRNAs (miRNAs) may reduce UGT1A activity by direct effects on the UGT1A 3’-UTR shared by all UGT1A enzyme transcripts, or by indirect effects on transcription factors regulating UGT1A expression. We performed an unbiased miRNA whole transcriptome association analysis using a bank of human livers with known acetaminophen glucuronidation activities. Of 754 miRNAs evaluated, 9 miRNAs were identified that were significantly overexpressed (p<0.05; >2-fold) in livers with low acetaminophen glucuronidation activities compared with those with high activities. miR-375 showed the highest difference (>10-fold), and was chosen for further mechanistic validation. We demonstrated using in silico analysis and luciferase reporter assays that miR-375 has a unique functional binding site in the 3’-UTR of the aryl hydrocarbon receptor (AhR) gene. Furthermore overexpression of miR-375 in LS180 cells demonstrated significant repression of endogenous AhR protein (by 40%) and mRNA (by 10%), as well as enzyme activity and/or mRNA of AhR regulated enzymes including UGT1A1, UGT1A6, and CYP1A2, without affecting UGT2B7, which is not regulated by AhR. Thus miR-375 is identified as a novel repressor of UGT1A-mediated hepatic acetaminophen glucuronidation through reduced AhR expression, which could predispose some individuals to increased risk for acetaminophen-induced ALF.
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DOI：
10.1124/jpet.113.210658
发表时间：
2014-03-01
影响因子：
3.5
作者：
Dluzen, Douglas F.;Sun, Dongxiao;Lazarus, Philip
通讯作者：
Lazarus, Philip
影响因子：
13.5
作者：
DEMORAIS, SMF;WELLS, PG
通讯作者：
WELLS, PG
DOI：
10.1124/jpet.112.202010
发表时间：
2013-05-01
影响因子：
3.5
作者：
Court, Michael H.;Freytsis, Marina;Lee, William M.
通讯作者：
Lee, William M.
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
MicroRNA解剖的生物信息学工具。
影响因子：
14.9
作者：
Akhtar MM;Micolucci L;Islam MS;Olivieri F;Procopio AD
通讯作者：
Procopio AD