Atf3, or Activating Transcription Factor 3, is a stress-induced transcription factor belonging to the ATF/CREB protein family. It acts as a transcription suppressor or activator by forming dimers with other ATF/CREB members. ATF3 is a key regulator in various biological processes, including metabolism, immunity, and cell-fate determination, and is involved in pathways such as NFκB, MAPK, and PI3K/AKT [4].

In abdominal aortic aneurysm (AAA), vascular smooth muscle cell-specific ATF3 knockdown in Ang II-induced AAA mice promoted AAA formation. ATF3 deficiency led to reduced vascular smooth muscle cell proliferation at the early stage of AAA via down-regulating PDGFRB, and increased mitochondria-dependent apoptosis at the advanced stage due to decreased BCL2 expression. NFKB1 inhibitor, andrographolide, inhibits ATF3 expression, ultimately leading to AAA development [1]. In atherosclerosis, its role is controversial. In endothelial cells, overexpression aggravates oxidative stress and inflammation, while in macrophages and liver cells, it can act as a negative regulator of inflammation and promote cholesterol metabolism [2]. In metabolic dysfunction-associated steatohepatitis (MASH), macrophage-specific Atf3 ablation in Western diet-fed mice exacerbated the disease, while overexpression protected against it. Atf3 regulated glucose-fatty acid cycle in macrophages, affecting hepatocyte steatosis and hepatic stellate cell fibrogenesis [3].

In conclusion, Atf3 is a crucial regulator in multiple biological processes and diseases. Gene-knockout mouse models, such as those used in AAA, atherosclerosis, and MASH studies, have revealed its role in cell-fate determination, inflammation, and metabolism. Understanding Atf3's function through these models may provide potential therapeutic strategies for these diseases.

References:

1. Wen, Ying, Liu, Yingying, Li, Qiang, Zhang, Yuan, Tang, Wai Ho. 2024. Spatiotemporal ATF3 Expression Determines VSMC Fate in Abdominal Aortic Aneurysm. In Circulation research, 134, 1495-1511. doi:10.1161/CIRCRESAHA.124.324323. https://pubmed.ncbi.nlm.nih.gov/38686580/

2. Wang, Bingyu, Yang, Xi, Sun, Xinyi, Lian, Jiangfang, Zhou, Jianqing. 2022. ATF3 in atherosclerosis: a controversial transcription factor. In Journal of molecular medicine (Berlin, Germany), 100, 1557-1568. doi:10.1007/s00109-022-02263-7. https://pubmed.ncbi.nlm.nih.gov/36207452/

3. Hu, Shuwei, Li, Rui, Gong, Dongxu, Wu, Huijuan, Xu, Yanyong. 2024. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis. In Science advances, 10, eado3141. doi:10.1126/sciadv.ado3141. https://pubmed.ncbi.nlm.nih.gov/39047111/

4. Ku, Hui-Chen, Cheng, Ching-Feng. 2020. Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer. In Frontiers in endocrinology, 11, 556. doi:10.3389/fendo.2020.00556. https://pubmed.ncbi.nlm.nih.gov/32922364/