Plasma free fatty acids and albumin in metabolic disease

肥胖导致血浆游离脂肪酸（FFA）浓度升高，并导致肝脏和骨骼肌游离脂肪酸供应过多。由此产生的组织脂质积累增加了胰岛素抵抗、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脂质摄取过多的问题，减少FFA供应的干预措施可能潜在地治疗肥胖的这些合并症。白蛋白是促进游离脂肪酸从脂肪转运到其他组织的主要循环蛋白。在评估预防代谢组织中胰岛素抵抗和脂质积累的潜在靶点时，初步实验表明，白蛋白敲除小鼠表现出血浆FFA减少、肝脏脂质降低和胰岛素敏感性改善。虽然在临床前和临床研究中，靶向脂肪分解来降低血浆游离脂肪酸的研究存在重大缺陷，但白蛋白是一个很有前景的治疗靶点。虽然白蛋白是体内常见的一种蛋白质，但ffa与白蛋白结合的部分抑制仍有望具有良好的耐受性，因为先天性白蛋白血症成人患者即使完全缺乏白蛋白，通常也仅伴有轻度或完全无症状。此外，初步研究表明，FFA-白蛋白相互作用可以通过内源性代谢物调节，这支持了FFA-白蛋白结合可以用小分子抑制剂靶向的观点。然而，关键的知识差距仍然存在，必须解决开发白蛋白作为代谢疾病的治疗靶点。通过减少血浆游离脂肪酸与白蛋白的结合来减少血浆游离脂肪酸是否可以预防或治疗肥胖代谢失调综合征，目前尚不清楚。据推测，减少血浆中白蛋白相关FFA的丰度将降低肥胖小鼠NAFLD病理程度、肌内脂质和胰岛素抵抗。如果该方法是有效的，未来可能会对ffa -白蛋白相互作用的特异性抑制剂有益。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血浆游离脂肪酸减少的影响。通过敲除小鼠白蛋白基因可降低血浆游离脂肪酸。为了提供新发现的背景，将结果与小鼠模型进行比较，该模型显示由于脂肪分解钝化（脂肪组织特异性敲除脂肪甘油三酯脂肪酶）导致血浆FFA减少。在Aim-2中，将研究相同的小鼠系，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，内源性小分子作为ffa -白蛋白结合的潜在抑制剂将通过体外生化分析和分子对接评估进行研究。阐明小分子对游离脂肪酸-白蛋白结合的影响将为未来的治疗策略铺平道路。该结果将加强对代谢疾病中脂质转运的科学理解，并且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.