J C Larkin1, S B Sears2, Y Sadovsky3. 1. Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. Electronic address: larkinjc@mail.magee.edu. 2. Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. 3. Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA, 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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.
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.
Authors: Caroline A Phelan; Joseph M Weaver; David J Steger; Shree Joshi; Jeffrey T Maslany; Jon L Collins; William J Zuercher; Timothy M Willson; Max Walker; Michael Jaye; Mitchell A Lazar Journal: Mol Endocrinol Date: 2008-07-31
Authors: Shawn Williams; Randy K Bledsoe; Jon L Collins; Sharon Boggs; Millard H Lambert; Ann B Miller; John Moore; David D McKee; Linda Moore; Jason Nichols; Derek Parks; Mike Watson; Bruce Wisely; Timothy M Willson Journal: J Biol Chem Date: 2003-05-07 Impact factor: 5.157
Authors: Sigrid Vondra; Victoria Kunihs; Tanja Eberhart; Karin Eigner; Raimund Bauer; Peter Haslinger; Sandra Haider; Karin Windsperger; Günter Klambauer; Birgit Schütz; Mario Mikula; Xiaowei Zhu; Alexander E Urban; Roberta L Hannibal; Julie Baker; Martin Knöfler; Herbert Stangl; Jürgen Pollheimer; Clemens Röhrl Journal: J Lipid Res Date: 2019-09-17 Impact factor: 5.922