Interaction of Choline and Fat in the Prenatal Programming of Nonalcoholic Steatohepatitis

胆碱和脂肪在非酒精性脂肪性肝炎产前规划中的相互作用

基本信息

批准号：
10627414
负责人：
Xinyin Jiang
金额：
$ 15.7万
依托单位：
BROOKLYN COLLEGE
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：
2023-07-19 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627414
关键词：
Affect Antioxidants Betaine Blood Glucose Characteristics Choline Choline Deficiency Custom DNA Methylation Data Development Diet Dietary Fats Dissociation Environment Epigenetic Process Exposure to Fatty acid glycerol esters Fetal Liver Fetus Fibrosis Fish Oils Food Fructose Funding Genes Glucose Intolerance Grant Health Hepatic High Fat Diet Inflammation Insulin Resistance Intake Intervention Joints Lactation Lecithin Life Lipids Lipoproteins Liver Long-Term Effects Metabolic Modernization Modification Mus Nutrient Obese Mice Obesity Oxidative Stress Phospholipids Plasmalogens Play Polyunsaturated Fatty Acids Population Predisposition Pregnancy Prevalence Prevention Process Prophylactic treatment Public Health Research Risk Factors Role Supplementation Triglycerides United States National Institutes of Health Weaning blood glucose regulation choline supplementation cognitive function compare effectiveness cost effective emerging adult epigenetic regulation fatty acid supplementation feeding hepatocyte injury high risk improved lard lipid biosynthesis lipid metabolism lipidomics maternal obesity methyl group neurogenesis nonalcoholic steatohepatitis obesogenic offspring postnatal postnatal period prenatal prevent promoter prophylactic protective effect risk mitigation simple steatosis stable isotope sugar synergism theories western diet

项目摘要

Summary Nonalcoholic steatohepatitis (NASH), characterized by hepatic triglyceride accumulation and inflammation, is a growing public health problem that affects about 7% of the U.S. population. It is hypothesized that maternal obesity exerts the first metabolic hit to the fetal liver, priming it for fat accumulation and increased susceptibility to NASH, whereas a postnatal obesogenic environment imposes further hits that result in NASH. In this proposal, we will use choline, a semi-essential nutrient, to prevent the prenatal programming of NASH. Choline plays an important role in lipid metabolism, facilitating hepatic lipid export and serving as a methyl donor which modifies expression of lipid metabolic genes via an epigenetic mechanism. Prior research of our lab suggests that maternal choline supplementation (MCS) in obese mouse dams prevented excess triglyceride accumulation in the fetal liver partly by increasing the DNA methylation of the lipogenic gene Srebf1 and improved blood glucose homeostasis in early adulthood. MCS also increased the abundance of long-chain polyunsaturated fatty acids (LC-PUFAs) containing plasmalogens, a group of phospholipids that serve as sacrificial antioxidants, in the offspring. Since the NASH liver is characterized by oxidative stress and LC-PUFA deficiency, MCS may mitigate these risk factors of NASH. Interestingly, the beneficial effects of MCS was more prominent in offspring whose dams also received high-fat (HF) feeding during gestation, suggesting an interaction between choline and HF feeding. The objective of this study is to determine the interactive effect of CS with dietary fat on preventing the prenatal programming of NASH. The overarching hypothesis is that prenatal and postnatal CS would ameliorate NASH development initiated by a maternal HF, obesogenic diet; CS would synergize with LC-PUFA supplementation to further prevent the prenatal programming of NASH. In Aim 1, we will determine the effect of lifelong choline supplementation (CS) on preventing the prenatal programming of NASH by HF feeding. Offspring mice born to HF-induced obese dams will receive a HF, high-fructose Western style diet (WD) post- weaning to trigger NASH. Choline will be supplemented at different life stages to discern its effect by timing of intervention during the prenatal period (first hit), postnatal period (later hits), or both (first and later hits). We will use stable isotope tracing to discern the preferential partitioning of choline into its metabolic fates as phosphatidylcholine or betaine, thereby influencing the hepatic lipidomic profile and epigenetic regulation later in life. In Aim 2, we will determine the effect of CS and LC-PUFA co-supplementation on NASH prevention. Both mouse dams and offspring will receive a fish oil supplemented HF or WD diet as well as CS. We will compare the joint effect of fish oil and CS on NASH characteristics and lipidomic profile. This study will provide proof-of-concept evidence for the use of choline alone or in combination with LC-PUFA as a cost-effective and innocuous prophylactic agent for NASH programmed by prenatal and postnatal HF, obesogenic diet exposures.

概括非酒精性脂肪性肝炎（NASH），其特征是肝脏甘油三酯积聚和炎症，是一个日益严重的公共卫生问题，影响着约 7% 的美国人口。据推测，母亲肥胖对胎儿肝脏产生第一个代谢打击，促进脂肪积累并增加易感性导致 NASH，而产后肥胖环境会进一步导致 NASH。在这个提案中，我们将使用胆碱（一种半必需营养素）来预防 NASH 的产前编程。胆碱在脂质代谢中发挥重要作用，促进肝脏脂质输出并作为甲基供体通过表观遗传机制改变脂质代谢基因的表达。我们实验室之前的研究表明肥胖小鼠母体补充胆碱（MCS）可防止甘油三酯过度积累在胎儿肝脏中，部分通过增加脂肪生成基因 Srebf1 的 DNA 甲基化来改善血液成年早期的葡萄糖稳态。 MCS 还增加了长链多不饱和脂肪的丰度含有缩醛磷脂的酸（LC-PUFA），缩醛磷脂是一组充当牺牲抗氧化剂的磷脂，后代。由于 NASH 肝脏的特点是氧化应激和 LC-PUFA 缺乏，MCS 可能减轻 NASH 的这些风险因素。有趣的是，MCS 的有益效果在后代中更为突出其母鼠在妊娠期间也接受了高脂肪（HF）喂养，这表明胆碱和胆碱之间存在相互作用高频喂食。本研究的目的是确定 CS 与膳食脂肪对预防 NASH 的产前规划。总体假设是产前和产后 CS 会改善由母亲 HF、致肥胖饮食引发的 NASH 发展； CS 与 LC-PUFA 具有协同作用补充以进一步预防 NASH 的产前编程。在目标 1 中，我们将确定效果终身补充胆碱（CS）对通过高频喂养预防 NASH 产前编程的影响。 HF 诱导的肥胖母鼠所生的后代小鼠将接受 HF、高果糖西式饮食 (WD)。断奶会引发 NASH。胆碱会在不同的生命阶段补充，以了解其效果。产前（首次打击）、产后（后续打击）或两者（首次和后续打击）期间进行干预。我们将使用稳定同位素示踪来辨别胆碱对其代谢命运的优先分配：磷脂酰胆碱或甜菜碱，从而影响肝脏脂质组学特征和随后的表观遗传调控在生活中。在目标 2 中，我们将确定联合补充 CS 和 LC-PUFA 对预防 NASH 的效果。小鼠母鼠和后代都将接受添加鱼油的 HF 或 WD 饮食以及 CS。我们将比较鱼油和 CS 对 NASH 特征和脂质组学特征的联合影响。这项研究将提供单独使用胆碱或与 LC-PUFA 结合使用作为具有成本效益和成本效益的概念验证证据通过产前和产后 HF、致肥胖饮食暴露来预防 NASH 的无害预防剂。