Exposure to complement induced preeclampsia promotes fetal steatosis

暴露于补体诱发的先兆子痫会促进胎儿脂肪变性

基本信息

批准号：
10740802
负责人：
Manu Banadakoppa
金额：
$ 16万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-02 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740802
关键词：
Accounting Adult Affect Bees Birth Weight Blood Circulation Body mass index Cardiovascular Diseases Child Childhood Cholesterol Cholesterol Esters Chylomicrons Coagulation Process Complement Control Groups Deposition Development Down-Regulation Environment Experimental Animal Model Exposure to Fatty Liver Fatty acid glycerol esters Female Fetal Development Fetal Growth Retardation Fetal Liver Fetus Fibrin Future Gene Expression Gene Expression Regulation Genes Gestational Age Growth Health Hepatic Hepatocyte High Density Lipoproteins Human Hypertension IL-6 inhibitor Impairment Laboratories Link Lipids Liver Liver Cirrhosis Liver Fibrosis Liver diseases Low-Density Lipoproteins Malnutrition Mediating Metabolic Metabolic Diseases Metabolic syndrome Mus Neonatal Nonesterified Fatty Acids Nutritional Obesity Outcome Study Overnutrition Pathway interactions Phenotype Physiological Placenta Pre-Eclampsia Pregnancy Pregnant Women Premature Mortality Prevalence Primary carcinoma of the liver cells Research Risk Risk Factors Rodent Sex Differences Signal Pathway Signal Transduction Source TNF gene Testing Time Tissue-Specific Gene Expression Triglycerides Up-Regulation Validation Very low density lipoprotein Woman comorbidity cytokine disorder risk fatty acid oxidation fetal gene repression inflammatory milieu inhibitor insight insulin secretion intrauterine environment lipid biosynthesis lipid metabolism liver metabolism liver transplantation male maternal obesity mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis nonhuman primate novel nutrition offspring oxidation postnatal pregnant prenatal prevent receptor sex uptake

项目摘要

Abstract: Now it is well recognized that exposure to adverse intrauterine environment can greatly affect the health postnatally and in adulthood. Exposure to maternal obesity during gestation is linked to offspring adiposity, premature mortality from cardiovascular disease and hepatic steatosis in humans. Evidence from different experimental animal models including rodents and non-human primates strongly suggests that exposure to maternal overnutrition during gestation promotes fetal hepatic fat storage (steatosis) with a long-lasting metabolic consequence for offspring. In contrast to steatosis in adults where increased hepatic de novo lipogenesis and decreased fatty acid oxidation are observed, steatosis in fetuses exposed to maternal obesity is predominantly due to increased transplacental fuel transfer since increased de novo lipogenesis is not observed in them. Increased hepatic de novo cholesterol synthesis and its decreased clearance were also observed in adult NAFLD/NASH. Regardless of the source of lipids, obesity associated steatosis in both prenatal and adults is characterized by overwhelming hepatic lipid load surpassing hepatocyte lipid metabolic contingency. In contrast to nutrition rich intrauterine environment of maternal obesity, PE is often associated with reduced nutritional supply to the developing fetus and consequent intrauterine growth restriction (IUGR). Prevalence of NAFLD is about 4 times higher in children after IUGR compared to those with normal birth weight. Adulthood NAFLD is independent of childhood body mass index and insulin secretion ruling out catch-up growth as the sole reason for NAFLD. The mechanism linking IUGR to adulthood NAFLD is not known. Under normal physiological conditions two important sources for liver lipids including cholesterol are de novo synthesis and receptor mediated import from blood circulation. Since liver is not a lipid storage depot, liver lipids are utilized in β-oxidation or secreted out mainly as very low-density lipoproteins (VLDL). Cholesterol is an obligate component of VLDL and required for VLDL secretion from the liver. Based on these observations we hypothesize that in IUGR fetuses steatosis occurs due to increased import of lipids accompanied by the deficiency of cholesterol and impaired VLDL secretion. Fetal liver steatosis could prime the liver for later liver metabolic diseases through similar mechanisms as involved in maternal obesity associated adulthood NAFLD. In this application we propose to understand fetal liver lipid metabolism under IUGR using a novel PE mouse model we recently developed in our laboratory.

抽象的：现在人们普遍认识到，暴露于不利的子宫内环境会极大地影响胎儿的发育。妊娠期间母亲肥胖与产后和成年期的健康状况有关。后代肥胖、心血管疾病和肝脂肪变性导致的过早死亡来自不同实验动物模型（包括啮齿动物和非人类）的证据。灵长类动物强烈表明，妊娠期间母体营养过剩会促进胎儿发育肝脏脂肪储存（脂肪变性），对后代产生长期持久的代谢后果。与成人脂肪变性相反，成人脂肪变性增加肝脏从头脂肪生成并减少脂肪观察到酸氧化，暴露于母亲肥胖的胎儿的脂肪变性主要是由于未观察到从头脂肪生成增加，因此经胎盘燃料转移增加其中，肝脏胆固醇从头合成增加，清除率降低。在成人 NAFLD/NASH 中观察到，无论脂质来源如何，肥胖相关的脂肪变性。在产前和成人中，其特征是压倒性的肝脂质负荷超过肝细胞脂质代谢偶发事件。与母亲肥胖的营养丰富的宫内环境相反，PE通常与发育中的胎儿的营养供应减少以及随之而来的宫内生长与 IUGR 后的儿童相比，NAFLD 的患病率大约高 4 倍。对于出生体重正常的人来说，成年期 NAFLD 与儿童体重指数无关。和胰岛素分泌排除了追赶性生长是 NAFLD 的唯一原因。正常生理条件下 IUGR 与成年 NAFLD 之间的联系尚不清楚（两种）。肝脏脂质（包括胆固醇）的重要来源是从头合成和受体由于肝脏不是脂质储存库，因此肝脏脂质是从血液循环介导的输入。用于β-氧化或主要作为极低密度脂蛋白（VLDL）分泌。是 VLDL 的必需成分，是肝脏分泌 VLDL 所必需的。我们观察到，在 IUGR 胎儿中，由于输入的增加而发生脂肪变性。脂质伴随胆固醇缺乏和胎儿肝脏分泌受损。脂肪变性可以通过与以下类似的机制为以后的肝脏代谢疾病做好准备：参与与成人 NAFLD 相关的孕产妇肥胖。在此应用中，我们建议使用一种新颖的方法来了解 IUGR 下的胎儿肝脏脂质代谢我们实验室最近开发了 PE 小鼠模型。