Hyperlipidemia Triggers Trophoblast Cell Dysfunction and Preeclampsia via the AMPK/GATA3/FTL Pathway

BACKGROUND: Preeclampsia, a severe pregnancy complication with an incompletely deciphered cause, is strongly associated with hyperlipidemia. Our previous studies demonstrated that FTL (ferritin light chain) expression was diminished in preeclampsia placentas and that FTL downregulation inhibited trophoblast invasiveness and migration while promoting apoptosis, contributing to preeclampsia development. However, the potential interplay between hyperlipidemia and FTL in the pathogenesis of preeclampsia, as well as the regulatory mechanism involved, remains to be elucidated. METHODS: We conducted Spearman correlation analysis, used a high-fat diet-fed mice model, cell culture, and molecular biology assays, including immunohistochemistry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays, to explore the impact of hyperlipidemia on the development of preeclampsia and to elucidate the molecular mechanisms involved. RESULTS: Pregnant women with preeclampsia presented elevated serum total cholesterol, triglycerides, and low-density lipoprotein, with reduced high-density lipoprotein. Similarly, high-fat diet-fed mice exhibited dyslipidemia and preeclampsia-like characteristics. FTL expression was reduced in the placentas of patients with preeclampsia and high-fat diet-fed pregnant mice. In vitro, palmitic acid treatment reduced FTL expression, increased oxidative stress, and impaired trophoblast migration and invasion. GATA3 (GATA binding protein 3) was predicted to be an upstream transcription factor for FTL, with its knockdown reducing and its overexpression increasing FTL levels. Further analysis indicated that palmitic acid suppressed FTL expression by inhibiting GATA3 nuclear translocation and that AMPK (AMP-activated protein kinase) activation rescued FTL expression and restored trophoblast function. CONCLUSIONS: This study revealed that high lipid levels contribute to preeclampsia by downregulating FTL through the AMPK-GATA3 pathway, highlighting potential therapeutic targets for preeclampsia management.