Plasma free fatty acids and albumin in metabolic disease

代谢疾病中的血浆游离脂肪酸和白蛋白

• 批准号: 10473918
• 负责人: Gregory C. Henderson
• 金额: $ 19.38万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473918
• 关键词: Address; Adipose tissue; Adult; Albumins; Behavior; Benchmarking; Binding; Binding Sites; Biochemical; Biological Assay; Blood Circulation; Blood Glucose; Chronic; Citrates; Clinical; Clinical Research; Data; Development; Diabetes Mellitus; Diet; Docking; Exercise; Exercise Tolerance; Exhibits; Fasting; Fatty Liver; Food Access; Functional disorder; Future; Gene Proteins; Gluconeogenesis; Growth; Health; Hepatic; High Fat Diet; Histidine; Hour; Human; Hydrophobicity; In Vitro; Incidence; Insulin Resistance; Intervention; Intramuscular; Kinetics; Knock-out; Knockout Mice; Knowledge; Lead; Lipase; Lipid Binding; Lipids; Lipolysis; Lipoproteins; Liver; Liver diseases; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Muscle; Myocardial dysfunction; Nature; Nicotinic Acids; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Pathology; Pathway interactions; Phenotype; Phenylalanine; Plasma; Positioning Attribute; Proteins; Proteomics; Pyruvate; Regulation; Risk; Series; Severities; Skeletal Muscle; Symptoms; System; Testing; Therapeutic; Tissues; Triglycerides; United States; Work; blood glucose regulation; comorbidity; drug action; drug development; effective therapy; energy balance; experimental study; feeding; glucose tolerance; improved; inhibitor/antagonist; innovation; insulin sensitivity; insulin signaling; insulin tolerance; knockout gene; lipid metabolism; lipid transport; metabolic phenotype; mouse model; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; obese person; obesity prevention; oxidation; preclinical study; prevent; protein expression; response; side effect; small molecule; small molecule inhibitor; stoichiometry; stressor; therapeutic development; therapeutic target; uptake

Obesity leads to elevated plasma free fatty acid (FFA) concentration and excessive supply of FFA to the liver and skeletal muscle. The resulting tissue lipid accumulation increases risk for insulin resistance, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. By directly addressing the problem of excessive lipid uptake in the liver and muscle, interventions that reduce FFA supply could potentially treat these comorbidities of obesity. Albumin is the primary protein in circulation that facilitates the transport of FFA from adipose to other tissues. In evaluating potential targets to prevent insulin resistance and lipid accumulation in metabolic tissues, preliminary experiments demonstrated that albumin knockout mice exhibit reduced plasma FFA, reduced hepatic lipids, and improved insulin sensitivity. While targeting lipolysis to reduce plasma FFA has encountered significant pitfalls in pre-clinical and clinical studies, albumin is a promising therapeutic target. While albumin is a common protein in the body, partial inhibition of FFA-binding to albumin is still expected to be well-tolerated, as even the complete absence of albumin in adults with congenital analbuminemia is typically associated with only mild or complete absence of symptoms. Furthermore, initial studies indicate that the FFA-albumin interaction can be modulated by endogenous metabolites, supporting the notion that FFA- albumin binding can be targeted with small molecule inhibitors. However, critical knowledge gaps remain that must be addressed to develop albumin as a therapeutic target for metabolic disease. It is not yet established if reducing plasma FFA by reducing its binding to albumin can prevent or treat the syndrome of metabolic dysregulation in obesity. It is hypothesized that reducing the abundance of albumin-associated FFA in plasma will decrease the degree of NAFLD pathology, intramuscular lipid, and insulin resistance in obese mice. If the approach is effective, specific inhibitors of FFA-albumin interaction may be beneficial in the future. In Aim-1, the effects of reduced plasma FFA will be studied in obese mouse models through assessment of insulin sensitivity, as well as molecular and biochemical responses in adipose tissue, liver, and muscle. Reduced plasma FFA will be achieved through albumin gene knockout in mice. To provide context for the novel findings, results will be compared to a mouse model that exhibits reduced plasma FFA resulting from blunted lipolysis (adipose tissue-specific knockout of adipose triglyceride lipase). In Aim-2 the same mouse lines will be studied to assess glycemic regulation during fasting and exercise, to assess tolerance to metabolic stressors. In Aim- 3, endogenous small molecules that are potential inhibitors of FFA-albumin binding will be studied using in vitro biochemical assays and molecular docking assessment. This elucidation of the impact of small molecules upon FFA-albumin binding will pave the way for future therapeutic strategies. The results will enhance scientific understanding of lipid trafficking in metabolic disease, and FFA-albumin binding may emerge as a therapeutic target for NAFLD, insulin resistance, and type 2 diabetes.

肥胖会导致血浆游离脂肪酸 (FFA) 浓度升高以及肝脏和骨骼肌的 FFA 供应过多。由此产生的组织脂质积累会增加胰岛素抵抗、非酒精性脂肪肝 (NAFLD) 和 2 型糖尿病的风险。通过直接解决肝脏和肌肉中脂质摄取过多的问题，减少 FFA 供应的干预措施可能会治疗这些肥胖合并症。白蛋白是循环中的主要蛋白质，可促进 FFA 从脂肪转运至其他组织。在评估防止代谢组织中胰岛素抵抗和脂质积累的潜在目标时，初步实验表明，白蛋白敲除小鼠表现出血浆 FFA 减少、肝脂质减少和胰岛素敏感性提高。虽然以脂肪分解为目标来减少血浆 FFA 在临床前和临床研究中遇到了重大缺陷，但白蛋白是一个有前途的治疗靶点。虽然白蛋白是体内常见的蛋白质，但部分抑制 FFA 与白蛋白的结合仍有望得到良好的耐受性，因为即使患有先天性无白蛋白血症的成人完全缺乏白蛋白，通常也只会出现轻微或完全没有症状。此外，初步研究表明，FFA-白蛋白相互作用可以通过内源代谢物调节，支持小分子抑制剂可以靶向FFA-白蛋白结合的观点。然而，为了开发白蛋白作为代谢疾病的治疗靶点，必须解决关键的知识差距。目前尚未确定通过减少血浆 FFA 与白蛋白的结合来减少其是否可以预防或治疗肥胖代谢失调综合征。据推测，减少血浆中白蛋白相关 FFA 的丰度将降低肥胖小鼠的 NAFLD 病理程度、肌内脂质和胰岛素抵抗。如果该方法有效，FFA-白蛋白相互作用的特异性抑制剂在未来可能会有所裨益。在 Aim-1 中，将通过评估胰岛素敏感性以及脂肪组织、肝脏和肌肉的分子和生化反应，在肥胖小鼠模型中研究减少血浆 FFA 的影响。通过敲除小鼠白蛋白基因，可以减少血浆 FFA。为了为新发现提供背景，我们将结果与小鼠模型进行比较，该模型表现出由于脂肪分解减弱（脂肪组织特异性敲除脂肪甘油三酯脂肪酶）而导致血浆 FFA 减少。在 Aim-2 中，将对相同的小鼠品系进行研究，以评估禁食和运动期间的血糖调节，以评估对代谢应激源的耐受性。在 Aim-3 中，将使用体外生化测定和分子对接评估来研究作为 FFA-白蛋白结合的潜在抑制剂的内源性小分子。阐明小分子对 FFA-白蛋白结合的影响将为未来的治疗策略铺平道路。这些结果将增强对代谢疾病中脂质运输的科学认识，FFA-白蛋白结合可能成为 NAFLD、胰岛素抵抗和 2 型糖尿病的治疗靶点。