Exposure to complement induced preeclampsia promotes fetal steatosis

摘要： 现在大家都认识到，暴露在不利的宫内环境中会极大地影响 出生后和成年后的健康。孕期暴露于母体肥胖与 子代肥胖、心血管疾病过早死亡和肝脏脂肪变性 人类。来自不同实验动物模型的证据，包括啮齿动物和非人类 灵长类动物强烈表明，在怀孕期间暴露于母体营养过剩会促进胎儿 肝脏脂肪储存(脂肪变性)，对后代产生长期的代谢后果。 与成人脂肪变性相反，脂肪变性增加了肝脏的新生脂肪生成，减少了脂肪 观察到酸氧化，暴露于母体肥胖的胎儿的脂肪变性主要是 由于未观察到新生脂肪生成增加，因此经胎盘的燃料转移增加 穿着它们。肝脏新生胆固醇合成增加，清除减少。 在成人NAFLD/NASH中观察。无论血脂的来源如何，肥胖都会导致脂肪变性 无论是产前还是成人，其特点都是肝脏脂肪负荷超标 肝细胞脂代谢偶发事件。 与母亲肥胖的营养丰富的宫内环境相比，PE往往与 对发育中的胎儿的营养供应减少，从而导致胎儿宫内生长 限制(IUGR)。与IUGR后相比，NAFLD在儿童中的患病率高出约4倍 给那些出生体重正常的人。成年非酒精性脂肪肝与儿童体重指数无关 胰岛素分泌排除了追赶增长是NAFLD的唯一原因。这一机制 IUGR与成年NAFLD之间的联系尚不清楚。在正常生理条件下，两个 包括胆固醇在内的肝脂的重要来源是从头合成和受体 从血液循环中中介输入。因为肝脏不是脂类储存库，所以肝脂是 用于β氧化或主要以极低密度脂蛋白(VLDL)的形式分泌。胆固醇 是极低密度脂蛋白的专有成分，是极低密度脂蛋白从肝脏分泌所必需的。基于这些 观察结果我们假设IUGR胎儿发生脂肪变性是由于增加了进口的 血脂伴有胆固醇缺乏和极低密度脂蛋白分泌受损。胎肝 脂肪变性可以使肝脏为以后的肝脏代谢疾病做好准备，其机制类似于 与母体肥胖相关的成年NAFLD。 在这项应用中，我们建议使用一种新的方法来了解IUGR下的胎儿肝脏脂肪代谢 本实验室新近研制的PE小鼠模型。

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.