Nr2e1, also known as TLX, is a nuclear receptor and transcription factor that plays a crucial role in multiple biological processes. It is an essential regulator of neural stem cell growth, and is involved in pathways related to cell proliferation, differentiation, and apoptosis. It has significant biological importance in development, especially in the central nervous system [5]. Genetic models, such as gene knockout (KO) mouse models, have been instrumental in studying its functions.

In Nr2e1-KO mice, Nr2e1 ablation promotes liver steatosis and systemic insulin resistance, suggesting it has a protective role in non-alcoholic fatty liver disease (NAFLD) [3]. In diet-induced obese Nr2e1-KO mice, despite lower body weight, there is increased inflammatory cytokines secretion, hyperlipidemia, and impaired insulin sensitivity, indicating Nr2e1 may be a target to improve insulin sensitivity in obesity [4]. In hepatocytes, Nr2e1-knockdown AML12 cells show increased lipotoxicity sensitivity, abnormal lipid metabolism gene expression, and augmented palmitate-induced oxidative stress [6]. In MIN6 cells, Nr2e1 knockdown leads to increased lipotoxicity sensitivity, decreased proliferation, cell-cycle arrest, and higher apoptosis rates [2]. In the context of brain tumors, Nr2e1 recruits LSD1 to demethylate histone at the Pten promoter, repressing Pten expression and promoting brain tumour initiating cell (BTIC) proliferation [1].

In conclusion, Nr2e1 has diverse essential biological functions. Model-based research, especially using Nr2e1 KO mouse models, has revealed its significance in various disease areas such as diabetes, NAFLD, obesity-related complications, and brain tumors. These findings suggest Nr2e1 could be a potential therapeutic target for these diseases.

References:

1. Hu, Rong, Hameed, Umar Farook Shahul, Sun, Xiang, Swaminathan, Kunchithapadam, Yuan, Ping. 2022. A NR2E1-interacting peptide of LSD1 inhibits the proliferation of brain tumour initiating cells. In Cell proliferation, 56, e13350. doi:10.1111/cpr.13350. https://pubmed.ncbi.nlm.nih.gov/36321378/

2. Shi, Xiaoli, Deng, Haohua, Dai, Zhe, Ma, Pei, Cheng, Jing. 2015. Nr2e1 Deficiency Augments Palmitate-Induced Oxidative Stress in Beta Cells. In Oxidative medicine and cellular longevity, 2016, 9648769. doi:10.1155/2016/9648769. https://pubmed.ncbi.nlm.nih.gov/26649147/

3. Xiong, Qing, Wu, Yuwen, Yang, Miao, He, Guangzhen, Xu, Yancheng. 2019. Nr2e1 ablation impairs liver glucolipid metabolism and induces inflammation, high-fat diets amplify the damage. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 120, 109503. doi:10.1016/j.biopha.2019.109503. https://pubmed.ncbi.nlm.nih.gov/31590127/

4. He, Guangzhen, Gu, Jiaowei, Wang, Huawei, Liu, Zheng, Xu, Yancheng. 2021. Nr2e1 deficiency aggravates insulin resistance and chronic inflammation of visceral adipose tissues in a diet-induced obese mice model. In Life sciences, 278, 119562. doi:10.1016/j.lfs.2021.119562. https://pubmed.ncbi.nlm.nih.gov/33915130/

5. Wang, Tao, Xiong, Jian-Qiong. 2016. The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases. In Neuroscience bulletin, 32, 108-14. doi:10.1007/s12264-015-0004-7. https://pubmed.ncbi.nlm.nih.gov/26769490/

6. Xiong, Qing, Wang, Huawei, Feng, Jieyuan, Wu, Guijun, Xu, Yancheng. 2024. Lack of Nr2e1 expression in hepatocytes impaired cell survival and aggravated palmitate-induced oxidative stress. In Advances in medical sciences, 69, 320-330. doi:10.1016/j.advms.2024.06.002. https://pubmed.ncbi.nlm.nih.gov/38901547/