Plasma free fatty acids and albumin in metabolic disease

肥胖会导致血浆游离脂肪酸(FFA)浓度升高，并导致肝脏和骨骼肌中FFA的过量供应。由此产生的组织脂质堆积增加了患胰岛素抵抗、非酒精性脂肪性肝病(NAFLD)和2型糖尿病的风险。通过直接解决肝脏和肌肉中过度摄取脂肪的问题，减少FFA供应的干预措施可能会治疗这些肥胖的共病。白蛋白是循环中的主要蛋白质，促进FFA从脂肪到其他组织的运输。在评估预防胰岛素抵抗和代谢组织中脂质堆积的潜在靶点时，初步实验表明，白蛋白基因敲除小鼠表现出血浆FFA降低，肝脏脂质降低，胰岛素敏感性提高。虽然以脂解为靶点来降低血浆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。虽然白蛋白是体内的一种常见蛋白质，但部分抑制FFA与白蛋白的结合仍有望得到很好的耐受性，因为即使患有先天性白蛋白血症的成年人完全缺乏白蛋白，通常也只与轻微或完全没有症状有关。此外，初步研究表明，FFA-白蛋白的相互作用可以被内源性代谢物调节，这支持了FFA-白蛋白结合可以通过小分子抑制剂来靶向的观点。然而，关键的知识差距仍然存在，必须加以解决，以开发白蛋白作为代谢性疾病的治疗靶点。通过减少血浆FFA与白蛋白的结合来降低血浆FFA是否可以预防或治疗肥胖症中的代谢紊乱综合征，目前还不确定。据推测，降低血浆中白蛋白相关FFA的丰度将减轻肥胖小鼠NAFLD的病理程度、肌内脂肪和胰岛素抵抗。如果这种方法是有效的，特定的FFA-白蛋白相互作用的抑制剂在未来可能是有益的。在AIM-1中，将通过评估胰岛素敏感性以及脂肪组织、肝脏和肌肉中的分子和生化反应来研究降低血浆FFA对肥胖小鼠模型的影响。白蛋白基因敲除可降低小鼠血浆游离脂肪酸水平。为了提供新发现的背景，结果将与钝化脂肪分解(脂肪组织特异性脂肪甘油三酯脂肪酶基因敲除)导致血浆FFA降低的小鼠模型进行比较。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，评估对代谢应激源的耐受性。在AIM-3中，将使用体外生化分析和分子对接评估来研究内源性小分子，这些小分子是FFA-白蛋白结合的潜在抑制剂。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。这些结果将加强对代谢性疾病中脂质运输的科学理解，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。

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.