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

基本信息

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
项目类别：
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

项目摘要

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.

肥胖导致血浆无脂肪酸（FFA）浓度升高，并向肝脏和骨骼肌供应过多。产生的组织脂质积累增加了胰岛素抵抗，非酒精性脂肪肝病（NAFLD）和2型糖尿病的风险。通过直接解决肝脏和肌肉中脂质过量摄取的问题，减少FFA供应的干预措施可能可能治疗这些肥胖的合并症。白蛋白是循环中的主要蛋白质，可促进FFA从脂肪转移到其他组织。在评估潜在靶标，以防止代谢组织中的胰岛素抵抗和脂质积累，初步实验表明，白蛋白敲除小鼠的血浆FFA降低，肝脂质降低并提高了胰岛素敏感性。在靶向脂肪分解以减少血浆FFA的同时，在临床前和临床研究中遇到了显着的陷阱，但白蛋白是一个有前途的治疗靶标。虽然白蛋白是体内常见的蛋白质，但对白蛋白的部分抑制作用仍然有望得到良好的耐受性，因为即使在先天性肛门血症的成年人中完全没有白蛋白，通常仅与轻度或完全没有症状有关。此外，初始研究表明，可以通过内源代谢物调节FFA-Albumin的相互作用，这支持了FFA-白蛋白结合可以用小分子抑制剂靶向的观念。但是，仍然需要解决关键的知识差距，以发展白蛋白作为代谢疾病的治疗靶点。如果通过减少与白蛋白的结合可以预防或治疗肥胖症代谢失调综合征的综合征，则尚不确定血浆FFA。假设减少血浆中白蛋白相关的FFA的丰度将降低肥胖小鼠中NAFLD病理学，肌内脂质和胰岛素抵抗的程度。如果该方法有效，则将来对FFA-Albumin相互作用的特定抑制剂可能会有益。在AIM-1中，通过评估胰岛素敏感性以及脂肪组织，肝脏和肌肉中的分子和生化反应，将研究肥胖小鼠模型中血浆FFA的影响。小鼠中的白蛋白基因敲除将实现减少的血浆FFA。为了提供新发现的背景，将将结果与小鼠模型进行比较，该模型表现出降低的血浆FFA，脂肪脂解（脂肪组织特异性敲除脂肪甘油三酸酯脂肪酶）的敲除）。在AIM-2中，将研究相同的小鼠系，以评估禁食和运动过程中血糖调节，以评估对代谢胁迫源的耐受性。在AIM-3中，将使用体外生化测定和分子对接评估来研究是FFA-α-α-蛋白结合的潜在抑制剂的内源性小分子。阐明小分子对FFA - α-α-结合的影响将为未来的治疗策略铺平道路。结果将增强对代谢疾病中脂质运输的科学理解，而FFA-Albumin结合可能会成为NAFLD，胰岛素抵抗和2型糖尿病的治疗靶点。