{"title":"Hyperlipidemia Triggers Trophoblast Cell Dysfunction and Preeclampsia via the AMPK/GATA3/FTL Pathway.","authors":"Hanhui Nie,Xiufang Wang,Lei Guo,Jiachun Wei,Yiling Wei,Yudie Gao,Jian Wang,Ka Cheuk Yip,Xiaman Huang,Qiao Zhang,Feng Gao,Ruiman Li","doi":"10.1161/hypertensionaha.125.24839","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nPreeclampsia, 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.\r\n\r\nMETHODS\r\nWe 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.\r\n\r\nRESULTS\r\nPregnant 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.\r\n\r\nCONCLUSIONS\r\nThis study revealed that high lipid levels contribute to preeclampsia by downregulating FTL through the AMPK-GATA3 pathway, highlighting potential therapeutic targets for preeclampsia management.","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"35 1","pages":""},"PeriodicalIF":6.9000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hypertension","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/hypertensionaha.125.24839","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.