The influence of ligand-activated LXR on primary human trophoblasts

Abstract Introduction The Liver X Receptors (LXRs) are critical transcriptional regulators of cellular metabolism that promote cholesterol efflux and lipogenesis in response to excess intracellular cholesterol. In contrast, the Sterol Response Element Binding Protein-2 (SREBP2) promotes the synthesi...

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Published in:	Placenta (Eastbourne) Vol. 35; no. 11; pp. 919 - 924
Main Authors:	Larkin, J.C, Sears, S.B, Sadovsky, Y
Format:	Journal Article
Language:	English
Published:	Kidlington Elsevier Ltd 01-11-2014 Elsevier
Subjects:	Biological and medical sciences Cell Differentiation Cells, Cultured Cholesterol - metabolism Embryology: invertebrates and vertebrates. Teratology Female Fetal Growth Retardation - etiology Fundamental and applied biological sciences. Psychology Gene Expression Humans Hydrocarbons, Fluorinated Hydroxycholesterols Internal Medicine Ligands Lipid Droplets - metabolism Liver X Receptors LXR Obstetrics and Gynecology Orphan Nuclear Receptors - metabolism Oxidation-Reduction Oxysterol Pregnancy Progesterone - metabolism SREBP2 Sterol Regulatory Element Binding Protein 2 - metabolism Sulfonamides T0901317 Trophoblast Trophoblasts - cytology Trophoblasts - metabolism SREBP2 Trophoblast T0901317 LXR Oxysterol Human Trophoblaste Vertebrata Mammalia Fetal membrane Ligand Primary
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Summary:	Abstract Introduction The Liver X Receptors (LXRs) are critical transcriptional regulators of cellular metabolism that promote cholesterol efflux and lipogenesis in response to excess intracellular cholesterol. In contrast, the Sterol Response Element Binding Protein-2 (SREBP2) promotes the synthesis and uptake of cholesterol. Oxysterols are products of cholesterol oxidation that accumulate in conditions associated with increased cellular levels of reactive oxygen species, such as hypoxia and oxidative stress, activating LXR and inhibiting SREBP2. While hypoxia and oxidative stress are commonly implicated in placental injury, the impact of the transcriptional regulation of cholesterol homeostasis on placental function is not well characterized. Methods We measured the effects of the synthetic LXR ligand T0901317 and the endogenous oxysterol 25-hydroxycholesterol (25OHC) on differentiation, cytotoxicity, progesterone synthesis, lipid droplet formation, and gene expression in primary human trophoblasts. Results Exposure to T0901317 promoted lipid droplet formation and inhibited differentiation, while 25OHC induced trophoblast toxicity, promoted hCG and progesterone release at lower concentrations with inhibition at higher concentrations, and had no effect on lipid droplet formation. The discrepant effect of these ligands was associated with distinct changes in expression of LXR and SREBP2 target genes, with upregulation of ABCA1 following 25OHC and T090317 exposure, exclusive activation of the lipogenic LXR targets SREBP1c, ACC1 and FAS by T0901317, and exclusive inhibition of the SREBP2 targets LDLR and HMGCR by 25OHC. Conclusion These findings implicate cholesterol oxidation as a determinant of trophoblast function and activity, and suggest that placental gene targets and functional pathways are selectively regulated by specific LXR ligands.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0143-4004 1532-3102
DOI:	10.1016/j.placenta.2014.09.002