The Liver X Receptor (LXR) and its Target Gene ABCA1 are Regulated Upon Low Oxygen in Human Trophoblast Cells: A Reason for Alterations in Preeclampsia?

Expression of LXRA and LXRB and their target genes for cholesterol transport are increased in the human placenta during pregnancy. (a–g) Bars show mRNA expression normalized to 18S rRNA in placental tissues of all trimesters of pregnancy. a, LXRA; b, LXRB; c, SRBI; d, LDLR; e, ABCG1; f, ABCA1; g, ABCG4. * denotes significant difference to the preceding age group (p ≤ 0.05; n = 6–10).

LXRA and ABCA1 mRNA expression in human placentae of preeclamptic patients compared to age-matched normal controls. a, mRNA expression of LXRA and ABCA1 in early-onset preeclamptic placentae (25–33 wk, n = 16) and their respective gestational age-matched controls (23–33 wk, n = 16); b, mRNA expression of LXRA and ABCA1 in late-onset preeclamptic placentae (34–39 wk, n = 15) and gestational age-matched control groups (control 2: 34–39 wk, n = 12). * indicates significant difference compared to control (MWU-test, p ≤ 0.05). - indicates the average per group.

LXRA and ABCA1 expression increased in the human placenta during gestation and ABCA1 protein expression is increased in early preeclamptic placentae. (a–c) Localization of LXRA (green) in human placental tissue of 1st trimester (8 wk, a), 2nd trimester (30 wk, c) and term placenta (38 wk, b). LXRA is mainly expressed in the cytotrophoblast, mesenchyme and endothelial cells of vessels as shown by co-localization with CD34 (red) (b). (e–g) Localization of ABCA1 (green) in human placental tissue in 1st trimester (8 wk, e), 2nd trimester (30 wk, g) and term placenta (38 wk, f). ABCA1 is expressed in the syncytiotrophoblast, cytotrophoblast, mesenchyme and endothelial cells of vessels as shown by co-localization with CD34 (red) (f) and placental macrophages (Hofbauer cells) co-labeled with the marker CD163 (red) (insert in f). (b, f) + DAPI staining of the nuclei (blue). yellow staining: merge. Localization of LXRA protein in age-matched normal control placental tissue (30 wk) (c) compared to early-onset preeclamptic placentae (early Pe, 30 wk) (d) showed no change in expression and localization. Interestingly localization of ABCA1 protein in early-onset preeclamptic placentae (31 wk, h) showed a stronger expression in the mesenchyme compared to matched control tissue (g). N = 4 different placentae of each experimental group. (i) Example of an immunoblot of ABCA1 expression in early-onset preeclamptic placentae (early PE) and matched normal controls. ABCA1 protein expression is significantly increased in preeclamptic placentae (n = 6) compared to age-matched controls (n = 4). * Different from control (p ≤ 0.05). Scale bar represents 80 μm.

Expression of LXRA, LXRB and their target gene ABCA1 in human JAr trophoblast cells treated with and without T0901317 upon normal and low oxygen levels. JAr cells were incubated with or without the LXR agonist T0901317 (1.0 μM) upon 20% O₂ and 1% O₂ conditions. a, LXRA; b, LXRB; c, ABCA1. mRNA expression was corrected for that of 18S rRNA. * Different from normoxic control (MWU-test, p ≤ 0.05).

ABCA1 mRNA expression in human placental explants is increased upon low oxygen, while LXRA and LXRB are unchanged. Human placental explants from 7 different donors were incubated under 20% O₂ and hypoxic conditions (3% O₂). mRNA expression of LXRA (a), LXRB (b) and ABCA1 (c) was corrected for that of β-actin. Data were analyzed in a pairwise way by Wilcoxon Signed Ranks Test.

ABCA1 mRNA expression in human placental explants is increased upon T0901317 treatment under 3% O₂. Human placental explants were treated with 1 μM T0901317 (n = 4) upon 3% O₂ compared to the untreated control (n = 3). Data were analyzed by MWU, single-sided significance.