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. 2025 Dec;57(1):2495763.
doi: 10.1080/07853890.2025.2495763. Epub 2025 Apr 29.

Role of oxysterol 4β-hydroxycholesterol and liver X receptor alleles in pre-eclampsia

Lassi Kaartinen  1   2 , Tiina Jääskeläinen  3   4 , Eeva Sliz  5 , Gamze Yazgeldi Gunaydin  6   7   8 , Satu Wedenoja  6   7   9 , Shintaro Katayama  6   7   8 , Eero Kajantie  2   10   11   12 , Valtteri Rinne  13 , Seppo Heinonen  9 , Juha Kere  6   7   8 , Heta Merikallio  1   2 ; Hannele Laivuori submitted on behalf of FINNPEC group; Eeva Sliz; submitted on behalf of FinnGen group; Hannele Laivuori  3   14   15   16 , Janne Hukkanen  1   2
Affiliations

Role of oxysterol 4β-hydroxycholesterol and liver X receptor alleles in pre-eclampsia

Lassi Kaartinen et al. Ann Med. 2025 Dec.

Abstract

Background: Liver X receptors (LXRs) are expressed in placenta and may be associated with pre-eclampsia (PE). Oxysterols act as agonists for LXRs. We recently proposed a new blood pressure-regulating circuit with oxysterol 4β-hydroxycholesterol (4βHC) acting as a hypotensive factor via LXRs.

Materials and methods: This study investigated the association between maternal plasma 4βHC, blood pressure (BP) indices, placental expression of LXR target genes, and patient characteristics using data from the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort. Plasma samples of 144 women with PE and 38 healthy pregnant controls as well as 44 PE and 40 control placental samples were available. In addition, genetic data from the FinnGen project was utilized to explore the associations of LXR alleles with PE and pregnancy hypertension.

Results: There were no significant associations between 4βHC and BP or maternal and perinatal characteristics in FINNPEC cohort. However, plasma 4βHC was inversely correlated with the maternal body mass index. There were no associations with the genetic variants of LXRs with PE in FinnGen. LXR target genes APOD, SCARB1, TGM2, and LPCAT3 were expressed differently between PE and normal pregnancies in placental samples of FINNPEC.

Conclusions: Our results demonstrate that plasma 4βHC and genetic LXR variants do not play a major role in PE and BP regulation during pregnancy. However, key LXR target genes involved in lipid metabolism were expressed differently in normal and PE pregnancies. Further research is needed to understand the complexities of oxysterols, LXRs, and their potential contributions to placental function and pregnancy outcomes.

Keywords: 4β-hydroxycholesterol; Liver X receptor; oxysterol; placenta; pre-eclampsia.

Plain language summary

Plasma 4βHC and genetic LXR variants do not play a major role in PE and BP regulation during pregnancy.Plasma 4βHC was inversely correlated with the maternal body mass index.The expression of LXR target genes APOD, TGM2, SCARB1 and LPCAT3 had significant difference between the PE and normal pregnancies.

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Conflict of interest statement

Valtteri Rinne is employed by Symeres Finland, operating under the brand name Admescope, and is a minor shareholder of Symeres. The other authors of this article declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Figures

Figure 1.
Figure 1.
Associations of the plasma 4βHC concentration and maternal BMI. Association between plasma 4βHC concentration and maternal BMI at the start of the pregnancy with all pregnancies (A) and maternal BMI at term with all pregnancies (B). Association of the plasma 4βHC and maternal BMI at the start of the pregnancy with only PE cases (C) and with maternal BMI at term with only PE cases (D). The red trendline represents the negative correlation between the 4βHC concentrations and maternal BMI. 4βHC 4β-hydroxycholesterol; BMI body mass index 4βHC 4β-hydroxycholesterol; BMI body mass index.
Figure 2.
Figure 2.
Differentially expressed genes in the LXR pathway in PE versus NP. Shown are significantly differentially expressed LXR genes (blue dots, padj < 0.05, DESeq2 Wald test) and non-significant genes (grey dots) in PE versus NP. The dashed line represents the significance threshold (padj = 0.05).
Figure 3.
Figure 3.
Differential expression of APOD, SCARB1, TGM2, and LPCAT3 between PE and NP conditions. Shown are the expression levels of APOD, SCARB1, TGM2, and LPCAT3, which were significantly different (padj < 0.05) between PE and NP conditions. Asterisks indicate statistical significance (*padj < 0.05, **padj < 0.01, ***padj < 0.001, ****padj < 0.0001).
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