Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia

Abstract

Background: The adipokine chemerin regulates adipogenesis and the metabolic function of both adipocytes and liver. Chemerin is elevated in preeclamptic women, and overexpression of chemerin in placental trophoblasts induces preeclampsia-like symptoms in mice. Preeclampsia is known to be accompanied by dyslipidemia, albeit via unknown mechanisms. Here, we hypothesized that chemerin might be a contributor to dyslipidemia.

Methods: Serum lipid fractions as well as lipid-related genes and proteins were determined in pregnant mice with chemerin overexpression in placental trophoblasts and chemerin-overexpressing human trophoblasts. In addition, a phospholipidomics analysis was performed in chemerin-overexpressing trophoblasts.

Results: Overexpression of chemerin in trophoblasts increased the circulating and placental levels of cholesterol rather than triglycerides. It also increased the serum levels of lysophosphatidic acid, high-density lipoprotein cholesterol (HDL-C), and and low-density lipoprotein cholesterol (LDL-C), and induced placental lipid accumulation. Mechanistically, chemerin upregulated the levels of peroxisome proliferator-activated receptor g, fatty acid-binding protein 4, adiponectin, sterol regulatory element-binding protein 1 and 2, and the ratio of phosphorylated extracellular signal-regulated protein kinase (ERK)1/2 / total ERK1/2 in the placenta of mice and human trophoblasts. Furthermore, chemerin overexpression in human trophoblasts increased the production of lysophospholipids and phospholipids, particularly lysophosphatidylethanolamine.

Conclusions: Overexpression of placental chemerin production disrupts trophoblast lipid metabolism, thereby potentially contributing to dyslipidemia in preeclampsia.

Keywords: Chemerin; Dyslipidemia; Phospholipids; Placenta; Preeclampsia; Trophoblast.

Fig. 1

Effect of overexpression of trophoblast-specific chemerin on mouse maternal lipid levels. Placentas and blood samples were collected from preeclampsia mice or controls on GD18. A Body weight of the pregnant mice. B Fasting glucose level. C Mouse placenta weight. Levels of (D) serum cholesterol, (E) triglycerides, (F) HDL-C levels, (G) LDL-C, and (H) lysophosphatidic acid levels, respectively. GD, gestation day; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. n = 5, *P < 0.05, **P < 0.01

Fig. 2

Effect of overexpression of trophoblast-specific chemerin on mouse placental lipid levels. Representative placental images of (A) hematoxylin and eosin staining (H&E, top panel: scale bar = 200 μm; Jz and Lab images: scale bar = 50 μm), (B) Oil Red O staining (top panel: scale bar = 200 μm; Jz and Lab images: scale bar = 50 μm), and (C) PPD staining (Bottom panel of Lab: scale bar = 20 μm; Jz and Lab images: scale bar = 50 μm), respectively. (D and E) Levels of (D) placental triglycerides and (E) cholesterol levels, respectively. n = 5, **P < 0.01. Jz, junctional zone; Lab, labyrinth zone; PPD, paraphenylenediamine

Fig. 3

Effect of chemerin overexpression on placental lipid metabolism. The mRNA expression of (A) Cmklr1, (B) Ccrl2, (C) Gpr1, (D) Pparg, Fabp4, and Srebp2 in placenta of mice at GD18. n = 5, *P < 0.05. E The expression of lipid metabolism-related proteins in placenta of mice at GD15 and GD18 by Western blot analysis. F The protein abundance was quantified and normalized to the level of β-actin or total ERK1/2. n = 5, *P < 0.05, **P < 0.01. A.U.: arbitrary units

Fig. 4

Effect of chemerin overexpression on lipid metabolism in HTR-8/SVneo cells. A Representative images of Oil Red O staining of HTR-8/SVneo cells (up panel: scale bar = 200 μm; Bottom panel: scale bar = 50 μm). The mRNA expression of (B) Chemerin and its receptors (GRP1 was not detected), (C) PPARg, (D) SREBP2, and (E) FABP4 in HTR-8/SVneo cells. n = 3, *P < 0.05. (F) Analysis of lipid metabolism in HTR-8/SVneo cells by using Western blot. G The protein abundance was quantified and normalized to the level of β-actin or total ERK1/2. n = 3 per group; *P < 0.05, **P < 0.01

Fig. 5

Phospholipidomics analysis of chemerin overexpression in HTR-8/SVneo cells. A Total levels of phospholipid classes in chemerin-overexpressing HTR-8/SVneo cells versus control cells. Contents of phospholipid molecular species for (B) LPC, LPE and LPG, (C) PS, (D) PC, (E) PE, and (F) PA, PG and PI in chemerin-overexpressing HTR-8/SVneo cells or control cells. LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPG, lyso phosphatidylglycerol; PA: phosphatidic acid; PC, phosphatidylcholine; PE: phosphatidylethanolamine; PG: phosphatidylglycerol; PI: phosphatidylinositol; PS: phosphatidylserine. n = 3 per group; *P < 0.05, **P < 0.01

Fig. 6

Schematic view of roles of chemerin in preeclampsia dyslipidemia. In preeclampsia condition, a high level of chemerin is released from trophoblasts in the placenta, inducing an inflammatory condition and further increasing the levels of placental lipids (TG, Chol, and phospholipids), lipid droplet accumulation, and the TCA cycle. Meanwhile, chemerin inhibits LDL uptake by reducing LDLR and SORT1 in trophoblasts, which leads to an increase in the release of lipids and the lipid-related protein (TG, Chol, phospholipids, and chemerin) from the placenta to maternal circulation, as well as a lower LDL uptake from circulation to placenta, eventually resulting in dyslipidemia in the patient (This figure with the credit “Created with BioRender.com.”)