Investigating the involvement of small intestine in metformin's effect on hepatic lipid metabolism

研究小肠参与二甲双胍对肝脏脂质代谢的影响

• 批准号: 10714498
• 负责人: Xiaojing Liu
• 金额: $ 39.76万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714498
• 关键词: 5' -AMP-activated protein kinase; Affect; Alkynes; Attenuated; Communication; Coupled; Data; Disease; Epithelial Cells; Fatty Liver; Fructose; Glucose; Goals; Hepatic; High Prevalence; Intestines; Isotopes; Knockout Mice; Knowledge; Lipids; Liquid Chromatography; Liver; Liver diseases; Mass Spectrum Analysis; Metabolic; Metabolic Diseases; Metabolism; Metformin; Methods; Molecular Target; Mus; Nature; Organ; Patients; Pharmaceutical Preparations; Pilot Projects; Reporting; Research; Resolution; Role; Site; Small Intestines; Testing; Tissues; dietary; fatty acid oxidation; fatty liver disease; in vivo; insight; intestinal epithelium; lipid biosynthesis; lipid metabolism; lipidomics; mass spectrometer; metabolomics; non-alcoholic fatty liver disease; pleiotropism; prevent; sugar

Project Summary Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), there are currently no approved medications to treat NAFLD. Metformin is frequently discussed as a promising treatment for NAFLD but reports on the efficacy of metformin in NAFLD patients are not consistent. Hence, the effect of metformin on hepatic lipid metabolism and the underlying mechanisms warrant further research. Metformin is thought to directly regulate hepatic lipid metabolism via activating hepatic AMP-activated protein kinase (AMPK), which subsequently inhibits de novo lipogenesis and promotes fatty acid oxidation in liver. However, there is a lack of quantitative assessment of to what extent hepatic lipogenesis or fatty acid oxidation is affected by metformin in vivo. In addition, due to high concentrations of metformin in the intestine, the intestine has emerged as an important action site of metformin. Dr. Huang generated intestinal epithelium-specific AMPK alpha 1 knockout mice and observed that the beneficial effect of metformin was attenuated in these mice (Nature Communications 2022), suggesting that the action of metformin in intestine is required for correcting dietary-induced metabolic disorders. Due to the pleiotropic effects of metformin, omics analysis such as metabolomics, lipidomics, and 13C isotope tracing will be required to quantitively and systemically assess the metabolic effects of metformin in different organs. In a pilot study, I performed metabolomics and lipidomics analysis using liquid chromatography coupled to high resolution mass spectrometer (LC-HRMS). The preliminary data suggest that the number of metabolites and lipids altered by metformin positively correlated with concentrations of metformin in these tissues, and metformin-induced metabolic and lipidomic changes were more profound in intestine due to the high concentration in intestine. We also synthesized a metformin probe containing an alkyne group, which will be used to identify the molecular target of metformin. In the next five years, I will combine my expertise in omics analysis with metformin probe and genetically modified mice developed by Dr. Huang to test the hypothesis that metformin induces beneficial metabolic and lipidomic alterations in intestine, enhances intestinal functions (e.g., sugar clearance) and subsequently shields liver from dietary-induced damage. The immediate goal of this project is to elucidate the action site and underlying mechanisms through which metformin protects the liver against high fructose-induced metabolic damage. The long-term goal is to 1) develop strategies to enhance the metabolic capacity of intestinal epithelial cells for alleviating liver steatosis and 2) to provide insights into identifying NAFLD patients who likely benefit from metformin monotherapy and developing optimal strategies to prevent or treat NAFLD. Even though this proposed study is focused on metformin in the context of dietary- induced liver disease, methods and discoveries in this study are expected to make a broad impact in diseases with dysregulated metabolism.

项目概要 尽管非酒精性脂肪性肝病（NAFLD）的患病率很高，但目前尚无批准的药物 治疗 NAFLD 的药物。二甲双胍经常被认为是治疗 NAFLD 的一种有前景的药物，但有报道称 关于二甲双胍治疗NAFLD患者的疗效并不一致。因此，二甲双胍对肝脂的影响 代谢及其潜在机制值得进一步研究。二甲双胍被认为可以直接调节 通过激活肝 AMP 激活蛋白激酶 (AMPK) 来调节肝脂质代谢，随后 抑制从头脂肪生成并促进肝脏脂肪酸氧化。但缺乏量化 评估体内二甲双胍对肝脏脂肪生成或脂肪酸氧化的影响程度。在 此外，由于肠道内二甲双胍浓度较高，肠道已成为重要的 二甲双胍的作用位点。黄博士培育出肠上皮特异性 AMPK α 1 基因敲除小鼠 观察到二甲双胍的有益作用在这些小鼠中减弱（Nature Communications 2022）， 表明二甲双胍在肠道中的作用是纠正饮食引起的代谢紊乱所必需的。 由于二甲双胍的多效性，代谢组学、脂质组学和 13C 同位素等组学分析 需要进行追踪来定量和系统地评估二甲双胍在不同人群中的代谢影响 器官。在一项试点研究中，我使用液相色谱耦合进行了代谢组学和脂质组学分析 高分辨率质谱仪 (LC-HRMS)。初步数据表明，代谢物的数量 二甲双胍改变的脂质与这些组织中二甲双胍的浓度呈正相关，并且 二甲双胍诱导的代谢和脂质组学变化在肠道中更为深远，因为二甲双胍的高浓度 肠道内浓度。我们还合成了含有炔基的二甲双胍探针，它将 用于识别二甲双胍的分子靶点。未来五年，我将结合我在组学方面的专业知识 使用二甲双胍探针和黄博士开发的转基因小鼠进行分析，以检验以下假设： 二甲双胍诱导肠道有益的代谢和脂质组学改变，增强肠道功能（例如， 糖清除），从而保护肝脏免受饮食引起的损害。此次活动的近期目标 该项目旨在阐明二甲双胍保护肝脏的作用位点和潜在机制 对抗高果糖引起的代谢损伤。长期目标是 1) 制定战略以增强 肠上皮细胞缓解肝脏脂肪变性的代谢能力，2) 提供见解 识别可能受益于二甲双胍单一疗法的 NAFLD 患者并制定最佳策略 预防或治疗 NAFLD。尽管这项拟议的研究重点是饮食背景下的二甲双胍 - 诱发性肝病、这项研究的方法和发现预计将对疾病产生广泛影响 新陈代谢失调。