Liver X receptor

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The Liver X Receptor is a family of the Nuclear Receptor which is vital for shaping the physiological development of mammals[1]. This receptor is further sub-divided into two types; Liver X Receptor α and ß[2]. This can be abbreviated to LXRα and LXRß. The LXR receptors are activated by oxysterols which are forms of modified cholesterol and are involved in the regulation of transcription of genes that process cholesterol in the body. This is vital for the maintenance of homeostatic levels of lipids, as well as other biomolecules in the body[3]. Both LXR receptors are steroid hormone receptors which are located in the nucleus and cytosol of cells[4].

Contents

LXRα

LXRα (Liver X Receptor Alpha) is a receptor that is predominantly found in several organs including the liver and kidneys[5]. This receptor has been the forefront of countless studies due to its involvement in the transcription of genes related to inflammation and the metabolism of biomolecules such as lipids and glucose[6]. Infact, the involvement of LXRα in the process of gene transcription has been linked to several diseases including; Diabetes Mellitus (Type II), Alzheimers and Atherosclerosis[7].

While it is not yet clear, LXRα has been linked to the regulation and tolerance of glucose metabolism pathways in several studies including one byLaffitte B et. al. The study showed that the addition of LXR agonists in mice suppressed gluconeogenesis in the liver and promoted the production of glucose kinase, therefore increasing the amount of glucose stored in the liver rather than being released into the bloodstream[8].

Since its discovery, LXRα has been known by several names including RLD-1 before being renamed to LXRα it is transcribed by the NR1H3 gene[9]

LXRß

LXR, known as the ubiquitous receptor , is found in tissues thorughout the entire body and is also involved in the lipogenesis pathways in the body[10].

Structure & Mechanism

The receptors are divided into several sections, including two domains; The DBD or DNA binding domain and the LBD or ligand binding domain, both of which are highly conserved sequences. Both LXR receptors don't work alone and will commonly form heterodimers with another receptor known as the RXR (retinoid X receptor)[11]. The receptor also has a hinge region. The DBD is covered by a repressor protein that is bound to it.

Once the oxysterol has bound to the hormone binding site of the receptor, it will undergo a conformational change, the conformational change affects the hinge region which moves allowing the repressor protein to be released freeing the DBD so it can bind to the LXRE sequence in the target gene[12]. Transcription of the target gene will occur if there is a ligand bound to the ligand binding domain that promotes transcription[13]. This heterodimer and ligand complex is only activated by hormones when cholesterol levels in the cell are elevated, in this case the target genes that are transcribed are genes that control the homeostatic levels of lipids in the cell through metabolic pathways[14]. Depending on which lipid is most abundant in the cell will also determine which genes are transcribed for example this transcription factor regulates the transcription of the gene that encodes for FAS (fatty acid synthase) this will synthesise fatty acids from other metabolites[15]. Once transcription is complete, the heterodimer complex is inactivated by protein kinase A which phosphorylates the receptor, once again, the receptor will undergo a conformational change and the DBD domain will be bound to a repressor protein so that it is unable to stay bound to the LXRE sequence in DNA[16][17].

References

  1. Alberts B, Bray D, Hopkin K, Johnson A, Lewis J, Raff M et al. Essential cell biology. 4th ed. New York: Garland Science; 2014.
  2. Tontonoz P, Mangelsdorf D. Liver X Receptor Signaling Pathways in Cardiovascular Disease. Molecular Endocrinology [Internet]. 2003;17(6):985-993. Available from: https://academic.oup.com/mend/article/17/6/985/2747382
  3. Tontonoz P, Mangelsdorf D. Liver X Receptor Signaling Pathways in Cardiovascular Disease. Molecular Endocrinology [Internet]. 2003;17(6):985-993. Available from: https://academic.oup.com/mend/article/17/6/985/2747382
  4. Alberts B, Bray D, Hopkin K, Johnson A, Lewis J, Raff M et al. Essential cell biology. 4th ed. New York: Garland Science; 2014.
  5. Revolvy L. "Liver X receptor alpha" on Revolvy.com [Internet]. Revolvy.com. 2017. Available from: https://www.revolvy.com/main/index.php?s=Liver%20X%20receptor%20alpha&item_type=topic
  6. Revolvy L. "Liver X receptor alpha" on Revolvy.com [Internet]. Revolvy.com. 2017 Available from: https://www.revolvy.com/main/index.php?s=Liver%20X%20receptor%20alpha
  7. Steffensen K, Gustafsson J. Putative Metabolic Effects of the Liver X Receptor (LXR). Diabetes [Internet]. 2004;53(Supplement 1):S36-S42. Available from: http://diabetes.diabetesjournals.org/content/53/suppl_1/S36
  8. Laffitte B, Chao L, Li J, Walczak R, Hummasti S, Joseph S et al. Activation of Liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proceedings of the National Academy of Sciences. 2003.100(9):5419-5424 Available from: http://www.pnas.org/content/100/9/5419.full.pdf
  9. Lin C, Vedin L, Steffensen K. The emerging roles of liver X receptors and their ligands in cancer. Expert opinion on therapeutic targets. 2016. 20(1):62. Available from: http://www.tandfonline.com/doi/pdf/10.1517/14728222.2015.1081169
  10. Song C, Kokontis J, Hiipakka R, Liao S. Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proceedings of the National Academy of Sciences [Internet]. 1994 ;91(23):10809-10813. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7971966?dopt=Abstract
  11. Lou X, Toresson G, Benod C, Suh J, Phillips K, Webb P et al. Structure of the retinoid X receptor α–liver X receptor β (RXRα–LXRβ) heterodimer on DNA. Nature [Internet]. 2014;21:277-281. Available from: https://www.nature.com/articles/nsmb.2778#main
  12. Mangelsdorf D, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K et al. The nuclear receptor superfamily: The second decade. Cell [Internet]. 1995;83(6):835-839. Available from: http://www.sciencedirect.com/science/article/pii/009286749590199X?via%3Dihub
  13. Lin C, Vedin L, Steffensen K. The emerging roles of liver X receptors and their ligands in cancer. Expert opinion on therapeutic targets. 2016; 20(1):62. Available from: http://www.tandfonline.com/doi/pdf/10.1517/14728222.2015.1081169
  14. Li A, Glass C. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. Journal of Lipid Research [Internet]. 2004;45(12):2161-2173. Available from: http://www.jlr.org/content/45/12/2161.full#sec-1
  15. Edwards P, Kennedy M, Mak P. LXRs;: Oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. Vascular Pharmacology [Internet]. 2002;38(4):249-256. Available from: http://www.sciencedirect.com/science/article/pii/S1537189102001751?via%3Dihub
  16. Yamamoto T, Shimano H, Inoue N, Nakagawa Y, Matsuzaka T, Takahashi A Et al. Protein Kinase A Suppresses Sterol Regulatory Element-binding Protein-1C Expression via Phosphorylation of Liver X Receptor in the Liver. Journal of Biological Chemistry [Internet]. 2007;282(16):11687-11695. Available from: http://www.jbc.org/content/282/16/11687.short
  17. Cheng H, Qi R, Paudel H, Zhu H. Regulation and Function of Protein Kinases and Phosphatases. Enzyme Research [Internet]. 2011; 2011:1-3. Available from: https://www.hindawi.com/journals/er/2011/794089/cta/
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