Nr1h3-KO Mouse

Nr1h3, also known as Liver X receptor α (LXRα), is a member of the nuclear receptor family. It plays a crucial role in regulating lipid metabolism, controlling macrophage polarization and the inflammatory response. By modulating lipid homeostasis, Nr1h3 is involved in various biological processes and is being investigated for its potential in treating human cancers, including lymphomas [1]. It may also be related to other functions like stem cell differentiation into hepatocytes [7].

In diffuse large B-cell lymphomas (DLBCL), Nr1h3 was found to be associated with the tumor microenvironment, especially highly expressed in M1-like pro-inflammatory macrophages. Patients with high Nr1h3 expression had longer survival, suggesting its potential as a prognostic biomarker [1]. In non-segmental vitiligo, the SNP rs3758672 in Nr1h3 was associated with disease susceptibility and therapeutic effects, with the A allele correlated with increased risk and poorer treatment response [2]. In multiple sclerosis, a missense mutation p.Arg415Gln in Nr1h3 was identified in families with severe and progressive disease, and common variants like rs2279238 increased the risk of progressive MS, with the mutant disrupting transcriptional activation [3,5]. In septic myocardial injury, silibinin pretreatment showed protective effects via activation of the Nr1h3 pathway, attenuating inflammation and oxidative stress [4]. In pulmonary tuberculosis patients, the mRNA expression of Nr1h3 was down-regulated [6]. In systemic lupus erythematosus, certain promoter polymorphisms of Nr1h3 were associated with disease susceptibility and regulation of its expression [8]. In colorectal cancer, Nr1h3 enhanced the inhibitory effect of LXR agonists on cell proliferation by down-regulating EGFR [9].

In conclusion, Nr1h3 is essential in regulating lipid metabolism, macrophage function, and inflammation. Its genetic variations and expression changes are associated with multiple diseases such as lymphomas, vitiligo, multiple sclerosis, sepsis-related heart injury, tuberculosis, systemic lupus erythematosus, and colorectal cancer. Research on Nr1h3, including through genetic models, has provided insights into its role in these diseases, potentially paving the way for new therapeutic strategies.

References:

1. Vegliante, Maria Carmela, Mazzara, Saveria, Zaccaria, Gian Maria, Pileri, Stefano A, Ciavarella, Sabino. 2022. NR1H3 (LXRα) is associated with pro-inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b-cell lymphoma. In Hematological oncology, 40, 864-875. doi:10.1002/hon.3050. https://pubmed.ncbi.nlm.nih.gov/35850118/

2. Xu, Meifeng, Xu, Qiuyu, Liu, Yan, Song, Yuning, Xiao, Shengxiang. 2023. Contributions of NR1H3 genetic polymorphisms to susceptibility and effects of narrowband UVB phototherapy to nonsegmental vitiligo. In Scientific reports, 13, 3384. doi:10.1038/s41598-023-30047-7. https://pubmed.ncbi.nlm.nih.gov/36854764/

3. Wang, Zhe, Sadovnick, A Dessa, Traboulsee, Anthony L, Song, Weihong, Vilariño-Güell, Carles. . Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. In Neuron, 90, 948-54. doi:10.1016/j.neuron.2016.04.039. https://pubmed.ncbi.nlm.nih.gov/27253448/

4. Sun, Meng, Zhao, Huadong, Jin, Zhenxiao, Zhang, Shaofei, Yang, Yang. 2022. Silibinin protects against sepsis and septic myocardial injury in an NR1H3-dependent pathway. In Free radical biology & medicine, 187, 141-157. doi:10.1016/j.freeradbiomed.2022.05.018. https://pubmed.ncbi.nlm.nih.gov/35640818/

5. Zhang, Yan, Wang, Longcai, Jia, Haiyang, Bao, Yunjuan, Liu, Guiyou. 2018. Genetic variants regulate NR1H3 expression and contribute to multiple sclerosis risk. In Journal of the neurological sciences, 390, 162-165. doi:10.1016/j.jns.2018.04.037. https://pubmed.ncbi.nlm.nih.gov/29801879/

6. Kumari, Anju, Saini, Varinder, Kumar, Vijay. 2024. Decreased mRNA expression of NR1H3 and ABCA1 in pulmonary tuberculosis patients from population of Punjab, India. In Molecular biology reports, 51, 657. doi:10.1007/s11033-024-09589-0. https://pubmed.ncbi.nlm.nih.gov/38740636/

7. Chen, Kai-Ting, Pernelle, Kelig, Tsai, Yuan-Hau, Guguen-Guillouzo, Christiane, Wang, Hsei-Wei. 2014. Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α. In Journal of hepatology, 61, 1276-86. doi:10.1016/j.jhep.2014.07.025. https://pubmed.ncbi.nlm.nih.gov/25073010/

8. Jeon, Ja-Young, Nam, Jin-Young, Kim, Hyoun-Ah, Bae, Sang-Cheol, Suh, Chang-Hee. 2014. Liver X receptors alpha gene (NR1H3) promoter polymorphisms are associated with systemic lupus erythematosus in Koreans. In Arthritis research & therapy, 16, R112. doi:10.1186/ar4563. https://pubmed.ncbi.nlm.nih.gov/24886807/

9. Liang, Xiaolong, Cao, Yi, Xiang, Song, Xiang, Zheng. 2019. LXRα-mediated downregulation of EGFR suppress colorectal cancer cell proliferation. In Journal of cellular biochemistry, 120, 17391-17404. doi:10.1002/jcb.29003. https://pubmed.ncbi.nlm.nih.gov/31104333/