Nr1h2, also known as LXRβ, is a member of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. It acts as a “cholesterol sensor” and plays a key role in regulating cholesterol and fatty acid metabolism by responding to the direct binding of cholesterol derivatives [2,4]. It is involved in various biological processes and has been implicated in multiple disease-related pathways. Genetic models, such as knockout mouse models, are valuable for studying its functions.

In the context of disease, studies have shown that Nr1h2 polymorphisms are associated with several conditions. For instance, in Iranian subjects, the polymorphisms rs28514894 and rs2303044 in Nr1h2 are significantly correlated with an increased risk of type-2 diabetes mellitus (T2DM) [1]. In a study on preeclampsia, the polymorphism rs2695121 in Nr1h2 was strongly associated with the disease, adding to the understanding of the link between cholesterol metabolism and preeclampsia [3]. In subjects of European ancestry at increased risk for T2DM, common variation within the Nr1h2 gene impaired insulin secretion, which may facilitate the development of T2DM [5]. Also, genetic variability at the Nr1h2 locus may contribute to the risk of Alzheimer's disease [6]. In mice, abrogation of Nr1h2 drastically reduces blastoid formation, indicating its role in blastoid and early embryo development [7]. In the K/BxN arthritis mouse model, Nr1h2/3-/-(double-deficient in Nr1h2 and Nr1h3) animals showed aggravated arthritis, highlighting the importance of Nr1h2 in modulating joint inflammatory response [8].

In conclusion, Nr1h2 is essential in regulating lipid metabolism and has implications in multiple disease areas including T2DM, preeclampsia, Alzheimer's disease, blastoid development, and rheumatoid arthritis. Gene-knockout and related mouse models have been crucial in revealing its role in these biological processes and disease conditions, providing insights into the underlying mechanisms and potential therapeutic targets.

References:

1. Sadeghi, Mohammad Bagher, Nakhaee, Alireza, Saravani, Ramin, Sargazi, Saman. 2021. Significant association of LXRβ (NR1H2) polymorphisms (rs28514894, rs2303044) with type 2 diabetes mellitus and laboratory characteristics. In Journal of diabetes and metabolic disorders, 20, 261-270. doi:10.1007/s40200-021-00740-3. https://pubmed.ncbi.nlm.nih.gov/34178836/

2. Russo-Savage, Lillian, Schulman, Ira G. 2021. Liver X receptors and liver physiology. In Biochimica et biophysica acta. Molecular basis of disease, 1867, 166121. doi:10.1016/j.bbadis.2021.166121. https://pubmed.ncbi.nlm.nih.gov/33713792/

3. Mouzat, Kevin, Mercier, Eric, Polge, Anne, Lumbroso, Serge, Gris, Jean-Christophe. 2011. A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia. In BMC medical genetics, 12, 145. doi:10.1186/1471-2350-12-145. https://pubmed.ncbi.nlm.nih.gov/22029530/

4. Jarvis, Sheba, Williamson, Catherine, Bevan, Charlotte L. 2019. Liver X Receptors and Male (In)fertility. In International journal of molecular sciences, 20, . doi:10.3390/ijms20215379. https://pubmed.ncbi.nlm.nih.gov/31671745/

5. Ketterer, Caroline, Müssig, Karsten, Machicao, Fausto, Häring, Hans-Ulrich, Staiger, Harald. 2010. Genetic variation within the NR1H2 gene encoding liver X receptor β associates with insulin secretion in subjects at increased risk for type 2 diabetes. In Journal of molecular medicine (Berlin, Germany), 89, 75-81. doi:10.1007/s00109-010-0687-1. https://pubmed.ncbi.nlm.nih.gov/21042792/

6. Adighibe, Omanma, Arepalli, Sampath, Duckworth, Jaime, Hardy, John, Wavrant-De Vrièze, Fabienne. 2005. Genetic variability at the LXR gene (NR1H2) may contribute to the risk of Alzheimer's disease. In Neurobiology of aging, 27, 1431-4. doi:. https://pubmed.ncbi.nlm.nih.gov/16207502/

7. Wong, Ka Wai, Zeng, Yingying, Tay, Edison, Li, Hu, Loh, Yuin-Han. 2024. Nuclear receptor-SINE B1 network modulates expanded pluripotency in blastoids and blastocysts. In Nature communications, 15, 10011. doi:10.1038/s41467-024-54381-0. https://pubmed.ncbi.nlm.nih.gov/39562549/

8. Domínguez-Luis, María Jesús, Castro-Hernández, Javier, Santos-Concepción, Sergio, Corr, Maripat, Díaz-González, Federico. 2024. Modulation of the K/BxN arthritis mouse model and the effector functions of human fibroblast-like synoviocytes by liver X receptors. In European journal of immunology, 54, e2451136. doi:10.1002/eji.202451136. https://pubmed.ncbi.nlm.nih.gov/39148175/