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

• 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
• 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

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），其特征是肝甘油三酸酯的积累和炎症， 是一个日益增长的公共卫生问题，影响了约7％的美国人口。假设母亲 肥胖症对胎儿肝脏发挥了第一次代谢命中，将其用于脂肪积累并增加易感性 纳什（Nash），而产后肥胖环境则施加了进一步的命中，导致纳什（Nash）。在此提案中， 我们将使用半必需的营养素胆碱来防止NASH的产前编程。胆碱 在脂质代谢，促进肝脂质出口并充当甲基供体中起着重要作用 通过表观遗传机制修饰脂质代谢基因的表达。我们实验室的事先研究建议 肥胖小鼠大坝中的母体胆碱补充（MCS）阻止了甘油三酸酯的积累过多 在胎儿肝脏中，部分通过增加脂肪生成基因SREBF1的DNA甲基化并改善了血液 成年初的葡萄糖稳态。 MC还增加了长链多不饱和脂肪的丰度 含有浆元的酸（LC-PUFA），一组用作牺牲抗氧化剂的磷脂，在 后代。由于NASH肝脏的特征是氧化应激和LC-PUFA缺乏，MC可能 减轻纳什的这些风险因素。有趣的是，MC的有益影响在后代更为突出 在妊娠期间，其大坝也接受了高脂（HF）的喂养，这表明胆碱与 HF进食。这项研究的目的是确定CS与饮食脂肪预防的互动效应 纳什的产前编程。总体假设是产前和产后CS 改善母体HF，肥胖饮食发起的NASH发育； CS将与LC-PUFA协同作用 补充以进一步防止纳什的产前编程。在AIM 1中，我们将确定效果 终身补充胆碱（CS），以防止通过HF喂养进行NASH的产前编程。 HF引起的肥胖大坝出生的后代小鼠将在后获得高果糖西方风格饮食（WD）。 断奶以触发纳什。胆碱将在不同的生活阶段补充，以通过 在产前期间（首次命中），产后（以后的命中）或两者（首次命中）的干预措施。我们 将使用稳定的同位素跟踪来辨别胆碱的优先分配为代谢命运 磷脂酰胆碱或甜菜碱，从而影响肝脂质组谱和表观遗传学调节 在生活中。在AIM 2中，我们将确定CS和LC-PUFA共补充对NASH预防的影响。 小鼠大坝和后代都将获得补充鱼油的HF或WD饮食以及CS。我们将 比较鱼油和CS对NASH特性和脂质组谱的关节作用。这项研究将提供 概念证据证明单独使用胆碱或与LC-PUFA结合使用作为具有成本效益的和 由产前和产后HF编程的NASH的无害预防剂，肥胖的饮食暴露。