Nr1h3, also known as Liver X receptor α (LXRα), is a key regulator involved in lipid metabolism. It controls macrophage (Mo) polarization and the inflammatory response by regulating lipid metabolism pathways [1]. LXRs play a significant role in various biological processes and are under clinical investigation for treating human cancers, including lymphomas [1]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying Nr1h3 functions.

In diffuse large B-cell lymphomas (DLBCL), Nr1h3 is associated with the tumor microenvironment, especially highly expressed in M1-like pro-inflammatory Mo, and can predict patient survival [1]. In non-segmental vitiligo, the SNP rs3758672 in Nr1h3 is related to disease susceptibility and therapeutic effects [2]. In multiple sclerosis, the NR1H3 p.Arg415Gln mutation and rs2279238 variant confer increased disease risk, and the mutant NR1H3 disrupts transcriptional regulation [3,5]. In septic myocardial injury, silibinin protects through an Nr1h3-dependent pathway, attenuating inflammation and oxidative stress [4]. In pulmonary tuberculosis, the mRNA expression of Nr1h3 is down-regulated [6]. In hepatocyte-like cell differentiation, Nr1h3 promotes hepatic maturation via an HNF4α-dependent reciprocal network [7]. In systemic lupus erythematosus, NR1H3 promoter polymorphisms are associated with disease susceptibility [8]. In Alzheimer's disease, genetic variation in Nr1h3 modulates the expression of LXRα and soluble Aβ42 levels [9].

In conclusion, Nr1h3 is crucial in lipid metabolism, macrophage regulation, and inflammation. Studies using KO/CKO mouse models (implied by the genetic-variant-function relationship studies) have revealed its significance in multiple disease areas, including lymphomas, vitiligo, multiple sclerosis, sepsis-related heart injury, tuberculosis, liver cell differentiation, systemic lupus erythematosus, and Alzheimer's disease. These findings contribute to understanding disease mechanisms and potentially developing 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. Natunen, Teemu, Martiskainen, Henna, Sarajärvi, Timo, Soininen, Hilkka, Hiltunen, Mikko. 2013. Effects of NR1H3 genetic variation on the expression of liver X receptor α and the progression of Alzheimer's disease. In PloS one, 8, e80700. doi:10.1371/journal.pone.0080700. https://pubmed.ncbi.nlm.nih.gov/24278306/