Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR.
Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR.
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DOI：
10.3390/metabo12090840
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发表时间：
2022-09-06
期刊：
影响因子：
4.1
通讯作者：
von Scheidt M
中科院分区：
文献类型：
--
作者：
Bauer S;Eigenmann J;Zhao Y;Fleig J;Hawe JS;Pan C;Bongiovanni D;Wengert S;Ma A;Lusis AJ;Kovacic JC;Björkegren JLM;Maegdefessel L;Schunkert H;von Scheidt M
Coronary artery disease (CAD) is a complex, multifactorial disease caused, in particular, by inflammation and cholesterol metabolism. At the molecular level, the role of tissue-specific signaling pathways leading to CAD is still largely unexplored. This study relied on two main resources: (1) genes with impact on atherosclerosis/CAD, and (2) liver-specific transcriptome analyses from human and mouse studies. The transcription factor activating transcription factor 3 (ATF3) was identified as a key regulator of a liver network relevant to atherosclerosis and linked to inflammation and cholesterol metabolism. ATF3 was predicted to be a direct and indirect (via MAF BZIP Transcription Factor F (MAFF)) regulator of low-density lipoprotein receptor (LDLR). Chromatin immunoprecipitation DNA sequencing (ChIP-seq) data from human liver cells revealed an ATF3 binding motif in the promoter regions of MAFF and LDLR. siRNA knockdown of ATF3 in human Hep3B liver cells significantly upregulated LDLR expression (p < 0.01). Inflammation induced by lipopolysaccharide (LPS) stimulation resulted in significant upregulation of ATF3 (p < 0.01) and subsequent downregulation of LDLR (p < 0.001). Liver-specific expression data from human CAD patients undergoing coronary artery bypass grafting (CABG) surgery (STARNET) and mouse models (HMDP) confirmed the regulatory role of ATF3 in the homeostasis of cholesterol metabolism. This study suggests that ATF3 might be a promising treatment candidate for lowering LDL cholesterol and reducing cardiovascular risk.
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影响因子：
30.8
作者：
Howson JMM;Zhao W;Barnes DR;Ho WK;Young R;Paul DS;Waite LL;Freitag DF;Fauman EB;Salfati EL;Sun BB;Eicher JD;Johnson AD;Sheu WHH;Nielsen SF;Lin WY;Surendran P;Malarstig A;Wilk JB;Tybjærg-Hansen A;Rasmussen KL;Kamstrup PR;Deloukas P;Erdmann J;Kathiresan S;Samani NJ;Schunkert H;Watkins H;CARDIoGRAMplusC4D;Do R;Rader DJ;Johnson JA;Hazen SL;Quyyumi AA;Spertus JA;Pepine CJ;Franceschini N;Justice A;Reiner AP;Buyske S;Hindorff LA;Carty CL;North KE;Kooperberg C;Boerwinkle E;Young K;Graff M;Peters U;Absher D;Hsiung CA;Lee WJ;Taylor KD;Chen YH;Lee IT;Guo X;Chung RH;Hung YJ;Rotter JI;Juang JJ;Quertermous T;Wang TD;Rasheed A;Frossard P;Alam DS;Majumder AAS;Di Angelantonio E;Chowdhury R;EPIC-CVD;Chen YI;Nordestgaard BG;Assimes TL;Danesh J;Butterworth AS;Saleheen D
通讯作者：
Saleheen D
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole
影响因子：
7.7
作者：
Kong, Qin;Zou, Jiahuan;Meng, Zhuo-Xian
通讯作者：
Meng, Zhuo-Xian
鉴定驱动小鼠F2间交叉中心血管和代谢表型的基因和网络。
影响因子：
3.7
作者：
Derry JM;Zhong H;Molony C;MacNeil D;Guhathakurta D;Zhang B;Mudgett J;Small K;El Fertak L;Guimond A;Selloum M;Zhao W;Champy MF;Monassier L;Vogt T;Cully D;Kasarskis A;Schadt EE
通讯作者：
Schadt EE
影响因子：
4.5
作者：
Bennett BJ;Davis RC;Civelek M;Orozco L;Wu J;Qi H;Pan C;Packard RR;Eskin E;Yan M;Kirchgessner T;Wang Z;Li X;Gregory JC;Hazen SL;Gargalovic PS;Lusis AJ
通讯作者：
Lusis AJ