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

• 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
• 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

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.

摘要： 现在，人们普遍认识到，暴露于不利的宫内环境会极大地影响胎儿的发育。 产后和成年期的健康。怀孕期间暴露于母体肥胖与以下因素有关： 后代肥胖，心血管疾病和肝脏脂肪变性导致的过早死亡， 人类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，在妊娠期暴露于母体营养过剩， 肝脏脂肪蓄积（脂肪变性），对后代具有持久的代谢后果。 与成人脂肪变性相反，成人脂肪变性中肝脏新生脂肪生成增加， 酸氧化，暴露于母体肥胖的胎儿脂肪变性主要是 由于没有观察到新生脂肪生成增加，经胎盘燃料转移增加 在他们身上。增加肝脏从头胆固醇合成和减少其清除率也 在成人NAFLD/NASH中观察到。无论脂质来源如何，肥胖相关脂肪变性 在产前和成人的特点是压倒性的肝脏脂质负荷超过 肝细胞脂质代谢偶然性。 与营养丰富的母体肥胖宫内环境相反，PE通常与 对发育中的胎儿的营养供应减少， 限制（IUGR）。IUGR后儿童NAFLD的患病率是IUGR后儿童NAFLD的4倍， 出生体重正常的人。成人NAFLD与儿童体重指数无关 和胰岛素分泌排除了追赶生长作为NAFLD的唯一原因。机制 IUGR与成年NAFLD之间的联系尚不清楚。在正常生理条件下， 肝脏脂质包括胆固醇的重要来源是从头合成和受体 介导的血液循环输入。由于肝脏不是脂质储存库， 用于β-氧化或主要作为极低密度脂蛋白（VLDL）分泌。胆固醇 是VLDL的专性组分，并且是VLDL从肝脏分泌所需的。基于这些 我们假设IUGR胎儿脂肪变性的发生是由于 脂质伴随胆固醇缺乏和VLDL分泌受损。胎肝 脂肪变性可以通过类似的机制， 与母亲肥胖相关的成年NAFLD。 在本申请中，我们建议使用一种新的方法来了解IUGR下的胎儿肝脏脂质代谢。 PE小鼠模型，我们最近在我们的实验室开发。