Cellular mechanisms of NLRP3 activation by ALCAT1 in diet-induced obesity

饮食诱导肥胖中 ALCAT1 激活 NLRP3 的细胞机制

• 批准号: 10658507
• 负责人: YUGUANG SHI
• 金额: $ 52.86万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658507
• 关键词: Ablation; Acyl Coenzyme A; Acyltransferase; Adipocytes; Adipose tissue; Attenuated; Autoimmune Diseases; Binding; CASP1 gene; Cardiolipins; Cell Aging; Cells; Chronic; Complications of Diabetes Mellitus; Data; Development; Disease; Docosahexaenoic Acids; Enzymes; Family; Health; Host Defense; Human; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Insulin Resistance; Interleukin-1 beta; Link; Macrophage; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Molecular; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Polymers; Polyunsaturated Fatty Acids; Prions; Production; Property; Proteins; Reactive Oxygen Species; Reporter; Role; Shapes; Signal Transduction; Sterility; Stimulus; System; Testing; Variant; Work; Yeasts; age related; cytokine; defense response; diet-induced obesity; functional loss; in vivo; inhibitor; marenostrin; microbial; misfolded protein; mitochondrial dysfunction; new therapeutic target; novel; obese patients; obesity treatment; oxidative damage; polymerization; prevent; prion-like; protein aggregation; response; senescence; sensor; sup35; transmission process

Obesity causes chronic “sterile” inflammation, which is implicated in insulin resistance and other metabolic complications. NLRP3 (NLR family pyrin domain containing 3) is an intracellular sensor for various “danger” signals from microbial infection and metabolic stress. Activation of NLRP3 inflammasomes elicits host defense responses by promoting caspase 1-dependent release of IL-1β and other pro-inflammatory cytokines. Intriguingly, activation of NLRP3 inflammasomes is also implicated in “sterile” inflammation and insulin resistance in diet-induced obesity (DIO), yet the “danger” signals that lead to NLRP3 activation in obesity remains elusive. Prions are misfolded proteins that are capable of self-transmitting their misfolded shape onto normal variants of the same protein. Recent progress in the field has identified more than 240 non-infectious prion-like proteins in mammals. Although a few of these proteins are well implicated in the pathogenesis of neurodegenerative diseases, surprisingly little information is known about majority of the prion-like proteins’ potential involvement in human health and disease. Here, we propose to investigate a novel pathway by which a putative prion-like protein regulates NLRP3 activation in DIO. This pathway is mediated by the ALCAT1 enzyme, the first acyl-CoA dependent lysocardiolipin acyltransferase previously identified by us. Our groundbreaking work in the field shows that ALCAT1 promotes the development of age-related metabolic diseases by catalyzing pathological remodeling of cardiolipin (CL) with very long-chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage (CL-Ox) by reactive oxygen species (ROS), leading to CL depletion and mitochondrial dysfunction in metabolic diseases. Remarkably, our preliminary studies also identified a pivotal role of ALCAT1 in linking DIO to NLRP3 activation as a putative prion-like protein, including 1) ALCAT1 forms prion-like protein aggregates in response to oxidative stress, which is mediated by a prion-like domain at the N-terminus; 2) ALCAT1 expression in adipose tissue is dramatically upregulated by DIO; and 3)Targeted deletion of ALCAT1 in adipocytes significantly attenuates NLRP3 activation by preventing macrophage infiltration in white adipose tissue. Together, these exciting findings let us to hypothesize that ALCAT1 promotes NLRP3 activation in DIO as a putative prion-like protein, which will be tested by three Specific Aims: AIM 1 will determine whether ALCAT1 promotes NLRP3 activation through mitochondrial dysfunction; AIM 2 will identify molecular mechanisms by which ALCAT1 promotes NLRP3 activation as a prion-like protein; and AIM 3 will assess whether ALCAT1 links cellular senescence in adipose tissue to chronic inflammation in DIO mice. Successful completion of the proposed studies will not only validate ALCAT1 as a novel drug target of chronic inflammation, but also provide proof of concept studies of targeting the enzyme for the treatment of obesity and its related complications.

肥胖会引起慢性“无菌”炎症，这在胰岛素抵抗和 其他代谢并发症。 NLRP3（NLR家族pyrin结构域3）是细胞内 来自微生物感染和代谢应激的各种“危险”信号的传感器。激活 NLRP3炎症体通过促进caspase 1依赖性引起宿主防御反应 IL-1β和其他促炎细胞因子的释放。有趣的是，nlrp3的激活 炎性症也与饮食引起的“无菌”炎症和胰岛素抵抗有关 肥胖（DIO），但是导致肥胖症中NLRP3激活的“危险”信号仍然难以捉摸。 王室是错误折叠的蛋白质，能够将其错误折叠的形状自我传播到 同一蛋白质的正常变体。该领域的最新进展已确定240多个 哺乳动物中的非感染风格样蛋白。尽管这些蛋白质中有几种实现了 在神经退行性疾病的发病机理中，有关的信息很少知道 大多数类似Prion的蛋白质潜在参与人类健康和疾病。在这里，我们 提议研究一种新的途径，假定的prion样蛋白调节NLRP3 激活DIO。该途径是由Alcat1酶介导的，这是第一个酰基辅酶A 先前由美国鉴定的溶液脂蛋白酰基转移酶。我们在现场开创性的工作 表明ALCAT1通过催化促进与年龄相关的代谢疾病的发展 用非常长链多不饱和脂肪酸的心脂蛋白（CL）的病理重塑，这种 如二十六烯酸（DHA）。 DHA的富集使Cl对氧化高度敏感 活性氧（ROS）损害（CL-OX），导致CL耗竭和线粒体 代谢疾病的功能障碍。值得注意的是，我们的初步研究也确定了关键 Alcat1在将DIO与NLRP3激活链接为推定的风prion样蛋白中的作用，包括1） Alcat1响应氧化应激而形成prion样蛋白聚集体，这是介导的 由N末端的王室样领域； 2）脂肪组织中的alcat1表达急剧 由Dio更新； 3）脂肪细胞中alcat1的靶向缺失显着减弱 NLRP3激活通过防止白脂肪组织中的巨噬细胞浸润。在一起，这些 令人兴奋的发现让我们假设Alcat1促进DIO中的NLRP3激活为 推定的类似prion的蛋白质，将通过三个特定目的进行测试：AIM 1将确定 Alcat1是否通过线粒体功能障碍促进NLRP3激活； AIM 2意志 确定Alcat1促进NLRP3激活作为prion样的分子机制 蛋白质; AIM 3将评估Alcat1是否将脂肪组织中的细胞感应联系到 DIO小鼠的慢性炎症。成功完成拟议的研究不仅将 验证alcat1是慢性炎症的新药物，但也提供了概念证明 靶向酶以治疗肥胖及其相关并发症的研究。