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.

Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia

“…Both LDLR and chemerin expression rely on the transcription factor SREBP2. 9,50 We observed that preeclamptic explants contained more SREBP2 and less LDLR at the protein level. Theoretically, this might shift the balance in favor of chemerin.…”

The Role of Chemerin in Metabolic and Cardiovascular Disease: A Literature Review of Its Physiology and Pathology from a Nutritional Perspective

“…The disturbed sFlt-1/VEGFa ratio involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Finally, extracellular signal-regulated kinase 1/2 (ERK1/2) upregulation might lead to lipid accumulation.Figure4summarizes the findings from references[110,158]. CMKLR1, chemerin-like receptor 1; CCRL2, CC motif chemokine receptor-like 2.…”

“…Additionally, chemerin levels were low in subfertile males, most likely due to their elevated luteinizing hormone levels [172], and this was suggested to reflect a link between chemerin and reproductive function. 4 summarizes the findings from references [110,158]. CMKLR1, chemerin-like receptor 1; CCRL2, CC motif chemokine receptor-like 2.…”

Understanding the Role of Chemerin in the Pathophysiology of Pre-Eclampsia

“…In a recently published study, Tan et al demonstrated in a mouse model that placental chemerin overexpression elevated maternal serum lipid level, leading to lipid accumulation in the placenta. Chemerin overexpression in this study was associated with increased levels of phospholipids, lysophospholipids, and cholesterol in both maternal blood and the placenta [ 111 ]. Lipid oxidation products (e.g., oxLDL) cause oxidative stress, endothelial dysfunction, and acute atherosclerosis [ 47 , 51 ].…”

“…That leads to the enhanced release of lipids and lipid-related proteins (triglycerides, cholesterol, phospholipids, and chemerin) from the placenta into the maternal circulation. On the other hand, chemerin causes also a lower LDL uptake from the circulation to the placenta, and this contributes to dyslipidemia in the patient [ 111 ]. Gu et al investigated the impact of chemerin overexpression on endothelial function, arterial stiffness, and early atherosclerosis in patients with hypertension and presented that a high chemerin serum level was an independent predictor of impaired endothelial function and increased arterial stiffness, even after adjustment for metabolic variables, inflammatory markers, and adipokines [ 112 ].…”