DLPC is a medium-chain phosphatidylcholine and an agonist ligand of liver receptor homolog-1 (LRH-1)[1]. DLPC occupies the LRH-1 ligand-binding pocket and activates LRH-1-dependent transcriptional programs governing bile-acid synthesis, glucose and lipid metabolism, endoplasmic-reticulum stress resolution, macrophage polarization, and cellular differentiation[1,2,3,6]. DLPC is used in research on nuclear-receptor signaling, metabolic homeostasis, hepatic stress, inflammation, diabetes-associated kidney injury, and nervous-system tumor biology.
In vitro, DLPC (100μM; 24h) activated LRH-1 and increased cytochrome P450 family 8 subfamily B member 1 (CYP8B1) expression in C3A/HepG2 hepatoma cells[1]. DLPC (50μM; 4 or 24h) increased interleukin 10, transforming growth factor beta 1, interleukin 1 receptor antagonist, mannose receptor, Dectin-1, and CD36 expression in mouse peritoneal macrophages and promoted the LRH-1/cytochrome P450/15-hydroxyeicosatetraenoic acid/peroxisome proliferator-activated receptor gamma axis associated with alternative macrophage polarization[3]. DLPC (100μM; 24h) increased perilipin 5 (PLIN5) messenger ribonucleic acid and protein in HepG2 cells without increasing LRH-1 protein and enhanced an LRH-1-regulated program linked to hepatic triglyceride metabolism[4].
In vivo, DLPC (100mg/kg/day; oral gavage once daily for 3 weeks) reduced serum glucose and hepatic triglycerides, improved glucose tolerance and insulin sensitivity, and decreased hepatic steatosis in db/db mice[1]. DLPC (100mg/kg; oral gavage every 12h for four doses, twice before and twice after a single 1mg/kg tunicamycin intraperitoneal injection) increased polo-like kinase 3 and activating transcription factor 2 signaling, reduced hepatic lipid accumulation and apoptosis, and accelerated endoplasmic-reticulum stress resolution in mice[2]. DLPC (100mg/kg; oral gavage once daily for 13 days) reduced U87-MG xenograft growth, Ki67-positive proliferating cells, phosphorylated histone H3-positive mitotic cells, Nestin, and Vimentin in non-obese diabetic/severe combined immunodeficiency mice without increasing cleaved caspase 3[5]. DLPC (100mg/kg; oral gavage once daily for 3 weeks) increased glomerular LRH-1 and glutaminase 2 (GLS2), enhanced glutamine-to-glutamate conversion, reduced urinary albumin-to-creatinine ratio, podocyte foot-process fusion, glomerular lesions, and apoptosis, and restored podocyte number in db/db mice[6].
References:[1] Lee JM, Lee YK, Mamrosh JL, Busby SA, Griffin PR, Pathak MC, et al. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature. 2011;474(7352):506-510. doi:10.1038/nature10111.
[2] Mamrosh JL, Lee JM, Wagner M, Stambrook PJ, Whitby RJ, Sifers RN, et al. Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution. eLife. 2014;3:e01694. doi:10.7554/eLife.01694.
[3] Lefevre L, Authier H, Stein S, Majorel C, Couderc B, Dardenne C, et al. LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARgamma ligand synthesis. Nat Commun. 2015;6:6801. doi:10.1038/ncomms7801.
[4] Pantha R, Lee JH, Bae JH, Koh EH, Shin M, Song DK, et al. Perilipin 5 is a novel target of nuclear receptor LRH-1 to regulate hepatic triglycerides metabolism. BMB Rep. 2021;54(9):476-481. doi:10.5483/BMBRep.2021.54.9.051.
[5] Gkikas D, Stellas D, Polissidis A, Manolakou T, Kokotou MG, Kokotos G, et al. Nuclear receptor NR5A2 negatively regulates cell proliferation and tumor growth in nervous system malignancies. Proc Natl Acad Sci U S A. 2021;118(39):e2015243118. doi:10.1073/pnas.2015243118.
[6] Hu J, Zhang Z, Hu H, Yang K, Zhu Z, Yang Q, et al. LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis. Cell Prolif. 2023;56(11):e13479. doi:10.1111/cpr.13479.