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.

肥胖会导致慢性“无菌”炎症，这与胰岛素抵抗和 其他代谢并发症 NLRP3（NLR 家族包含 3 个热蛋白结构域）是一种细胞内蛋白。 来自微生物感染和代谢应激激活的各种“危险”信号的传感器。 NLRP3 炎症小体通过促进 caspase 1 依赖性引发宿主防御反应 有趣的是，IL-1β 和其他促炎细胞因子的释放，以及 NLRP3 的激活。 炎症小体还与饮食引起的“无菌”炎症和胰岛素抵抗有关 肥胖（DIO），但导致肥胖中 NLRP3 激活的“危险”信号仍然难以捉摸。 朊病毒是错误折叠的蛋白质，能够将其错误折叠的形状自我传递到 该领域的最新进展已鉴定出 240 多种相同蛋白质的正常变体。 尽管其中一些蛋白质与哺乳动物中的非传染性朊病毒样蛋白质有关。 在神经退行性疾病的发病机制中，令人惊讶的是，我们对以下方面的信息知之甚少： 大多数朊病毒样蛋白与人类健康和疾病的潜在关系。 提议研究一种假定的朊病毒样蛋白调节 NLRP3 的新途径 DIO 中的激活是由第一个酰基辅酶 A 依赖性酶 ALCAT1 介导的。 我们之前在该领域发现了溶心磷脂酰基转移酶。 表明 ALCAT1 通过催化促进与年龄相关的代谢疾病的发展 心磷脂（CL）与超长链多不饱和脂肪酸的病理重塑，例如 作为二十二碳六烯酸 (DHA)，DHA 的富集使得 CL 对氧化高度敏感。 活性氧 (ROS) 损伤 CL-Ox，导致 CL 耗尽和线粒体 值得注意的是，我们的初步研究还发现了一个关键因素。 ALCAT1 在将 DIO 与 NLRP3 激活联系起来（作为推定的朊病毒样蛋白）方面的作用，包括 1) ALCAT1 响应氧化应激形成朊病毒样蛋白聚集体，这是介导的 2) 脂肪组织中 ALCAT1 的表达显着增加； DIO 上调；3) 脂肪细胞中 ALCAT1 的靶向缺失显着减弱 通过阻止白色脂肪组织中的巨噬细胞浸润来激活 NLRP3。 令人兴奋的发现让我们认为 ALCAT1 促进 DIO 中 NLRP3 的激活 假定的朊病毒样蛋白，将通过三个特定目标进行测试：AIM 1 将确定 ALCAT1 是否会通过线粒体功能障碍促进 NLRP3 激活； 确定 ALCAT1 作为朊病毒样促进 NLRP3 激活的分子机制 蛋白质；AIM 3 将评估 ALCAT1 是否与脂肪组织中的细胞衰老有关 DIO 小鼠的慢性炎症不仅能够成功完成所提出的研究。 验证 ALCAT1 作为慢性炎症的新型药物靶点，同时也提供概念证明 靶向酶治疗肥胖及其相关并发症的研究。