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.

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