Rxra, short for Retinoic acid X receptor alpha, is a member of the nuclear receptor superfamily. It is involved in multiple crucial biological processes such as lipid, glucose, energy, and hormone metabolism [3]. Rxra often functions as part of heterodimers with 14 other nuclear receptors, including peroxisome proliferator-activated receptors (PPARs), regulating transcription [6].

In mice, deletion of Rxra and Rxrb has been shown to augment leukemic growth, indicating its role in myeloid maturation [1]. In a sheep model of maternal undernutrition, the PPARA/RXRA signalling pathway was found to regulate hepatic lipid metabolism, with NEFAs activating PPARA signalling and BHBA inhibiting RXRA signalling [5]. In an atherosclerotic mice model, an SGLT2 inhibitor dapagliflozin was suggested to interact with the Rxra protein, suppressing the RXRA-PPARα-FABP4 signalling pathway and alleviating vascular cellular aging [4]. In human lung adenocarcinoma mouse models, CCL28 recruited pericytes that promoted vascular normalization after anti-angiogenesis therapy through the RA/RXRA/ANGPT1 pathway [2].

In conclusion, Rxra is essential for processes like myeloid maturation, lipid metabolism, vascular normalization, and may be a key player in diseases such as leukemia, atherosclerosis, and lung adenocarcinoma. Mouse models, including gene knockout and conditional knockout models, have been crucial in uncovering these functions and disease-related roles of Rxra, providing insights into potential therapeutic targets.

References:

1. Di Martino, Orsola, Ferris, Margaret A, Hadwiger, Gayla, Ricote, Mercedes, Welch, John S. 2022. RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells. In Haematologica, 107, 417-426. doi:10.3324/haematol.2021.278603. https://pubmed.ncbi.nlm.nih.gov/34134472/

2. Chen, Ying, Zhang, Zhiyong, Pan, Fan, Li, Yan, Huang, Guichun. 2024. Pericytes recruited by CCL28 promote vascular normalization after anti-angiogenesis therapy through RA/RXRA/ANGPT1 pathway in lung adenocarcinoma. In Journal of experimental & clinical cancer research : CR, 43, 210. doi:10.1186/s13046-024-03135-3. https://pubmed.ncbi.nlm.nih.gov/39075504/

3. Pan, Ziyi, Li, Xuewen, Wu, Dongsheng, Jin, Sihua, Geng, Zhaoyu. 2023. The Duck RXRA Gene Promotes Adipogenesis and Correlates with Feed Efficiency. In Animals : an open access journal from MDPI, 13, . doi:10.3390/ani13040680. https://pubmed.ncbi.nlm.nih.gov/36830469/

4. Zhang, Weiwei, Wang, Linghuan, Wang, Yujia, Ma, Yan, Cao, Feng. 2024. Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model. In Science China. Life sciences, 67, 2678-2691. doi:10.1007/s11427-024-2602-7. https://pubmed.ncbi.nlm.nih.gov/39225895/

5. Xue, Yanfeng, Guo, Changzheng, Hu, Fan, Zhu, Weiyun, Mao, Shengyong. 2019. PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1865, 158548. doi:10.1016/j.bbalip.2019.158548. https://pubmed.ncbi.nlm.nih.gov/31676441/

6. Halstead, Angela M, Kapadia, Chiraag D, Bolzenius, Jennifer, Bowman, Gregory R, Arora, Vivek K. 2017. Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation. In eLife, 6, . doi:10.7554/eLife.30862. https://pubmed.ncbi.nlm.nih.gov/29143738/