Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2.
Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2.
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DOI：
10.1038/srep35503
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发表时间：
2016-10-18
影响因子：
4.6
通讯作者：
Rodionov RN
中科院分区：
文献类型：
--
作者：
Burdin DV;Kolobov AA;Brocker C;Soshnev AA;Samusik N;Demyanov AV;Brilloff S;Jarzebska N;Martens-Lobenhoffer J;Mieth M;Maas R;Bornstein SR;Bode-Böger SM;Gonzalez F;Weiss N;Rodionov RN
循环中不对称和对称二甲基精氨酸(ADMA和SDMA)水平升高可预测并可能导致心血管疾病的终末器官损害。丙氨酸乙醛酸氨基转移酶2(AGXT2)调节全身ADMA和SDMA的水平，也调节脂代谢的调节剂β-氨基异丁酸(BAIB)的水平。我们在AGXT2启动子序列中发现了一个与肝核因子4α(HNF4α)可能的结合位点。在荧光素酶报告实验中，我们发现在破坏HNF4α结合位点后，Agxt2核心启动子的活性下降了75%。染色质免疫沉淀实验证实hNF4α与Agxt2启动子直接结合。SiRNA介导的HNF4a基因敲除导致HEPA 1-6细胞Agxt2基因表达水平降低近50%。与野生型相比，肝脏特异性HNF4a基因敲除小鼠的肝脏Agxt2表达和活性降低了90%，血浆ADMA、SDMA和BAIB水平升高。因此，我们确定HNF4α是Agxt2表达的主要调节因子。考虑到人类HNF4a基因多态性与2型糖尿病风险增加之间的强烈关联，我们目前的研究结果表明，由于HNF4α缺乏导致AGXT2下调以及随后的二甲基精氨酸和BAIB代谢障碍，可能与糖尿病患者心血管并发症的发生有关。
Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1–6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.
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影响因子：
6.9
作者：
Begriche, Karima;Massart, Julie;Fromenty, Bernard
通讯作者：
Fromenty, Bernard
全基因组关联研究的荟萃分析确定了东亚人 2 型糖尿病的 8 个新位点
影响因子：
30.8
作者：
Cho, Yoon Shin;Chen, Chien-Hsiun;Hu, Cheng;Long, Jirong;Ong, Rick Twee Hee;Sim, Xueling;Takeuchi, Fumihiko;Wu, Ying;Go, Min Jin;Yamauchi, Toshimasa;Chang, Yi-Cheng;Kwak, Soo Heon;Ma, Ronald C. W.;Yamamoto, Ken;Adair, Linda S.;Aung, Tin;Cai, Qiuyin;Chang, Li-Ching;Chen, Yuan-Tsong;Gao, Yutang;Hu, Frank B.;Kim, Hyung-Lae;Kim, Sangsoo;Kim, Young Jin;Lee, Jeannette Jen-Mai;Lee, Nanette R.;Li, Yun;Liu, Jian Jun;Lu, Wei;Nakamura, Jiro;Nakashima, Eitaro;Ng, Daniel Peng-Keat;Tay, Wan Ting;Tsai, Fuu-Jen;Wong, Tien Yin;Yokota, Mitsuhiro;Zheng, Wei;Zhang, Rong;Wang, Congrong;So, Wing Yee;Ohnaka, Keizo;Ikegami, Hiroshi;Hara, Kazuo;Cho, Young Min;Cho, Nam H.;Chang, Tien-Jyun;Bao, Yuqian;Hedman, Asa K.;Morris, Andrew P.;McCarthy, Mark I.;Takayanagi, Ryoichi;Park, Kyong Soo;Jia, Weiping;Chuang, Lee-Ming;Chan, Juliana C. N.;Maeda, Shiro;Kadowaki, Takashi;Lee, Jong-Young;Wu, Jer-Yuarn;Teo, Yik Ying;Tai, E. Shyong;Shu, Xiao Ou;Mohlke, Karen L.;Kato, Norihiro;Han, Bok-Ghee;Seielstad, Mark
通讯作者：
Seielstad, Mark
影响因子：
7.7
作者：
Johansson, Stefan;Raeder, Helge;Njolstad, Pal Rasmus
通讯作者：
Njolstad, Pal Rasmus
DOI：
10.1161/atvbaha.113.301219
发表时间：
2013-11-01
影响因子：
8.7
作者：
Gore, M. Odette;Lueneburg, Nicole;Boeger, Rainer H.
通讯作者：
Boeger, Rainer H.
影响因子：
4.8
作者：
Eeckhoute, J;Moerman, E;Laine, B
通讯作者：
Laine, B