Effects of Cholesterol in Pancreatic Islets

胆固醇对胰岛的影响

• 批准号: 10562987
• 负责人: Sakeneh Zraika
• 金额: $ 41.73万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562987
• 关键词: Ablation; Address; Adult; Beta Cell; Cardiovascular Diseases; Cell Death; Cell Survival; Cell membrane; Cell physiology; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Cytochrome P450; Data; Defect; Dependovirus; Development; Enzymes; Equilibrium; Exposure to; Functional disorder; Genes; Genetic; Human; Impairment; In Vitro; Inner mitochondrial membrane; Insulin; Islets of Langerhans; Knowledge; Lead; Literature; Mediating; Mediator; Messenger RNA; Metabolism; MicroRNAs; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Patients; Pharmaceutical Preparations; Play; Process; Protein Overexpression; Proteins; Quality Control; Repression; Research; Risk; Role; Structure of beta Cell of islet; Time; Toxic effect; cell type; differential expression; gene therapy; improved; in vivo; inhibitor; innovation; insulin secretion; islet; mitochondrial dysfunction; new therapeutic target; optogenetics; overexpression; response; risk mitigation; steroidogenic acute regulatory protein; trend

PROJECT SUMMARY/ABSTRACT Statins are the most commonly used cholesterol-lowering medication; however, statins increase the risk of new-onset type 2 diabetes (T2D). While this increased risk includes a direct effect of statins to impair islet β- cell function, the underlying mechanisms remain unclear. With statin use trending up among U.S. adults, there is an urgent need to better understand how statins lead to demise of the β cell – this knowledge will inform strategies aimed at reducing progression to T2D in patients on statin therapy. To this end, we have generated data that show a previously unrecognized effect of statins to promote mitochondrial cholesterol accumulation within islets. Surprisingly, there is almost no literature on mechanisms regulating mitochondrial cholesterol content in β cells. This knowledge gap will be addressed in the proposed studies, which focus on the role of cholesterol transport to mitochondria and its subsequent metabolism in statin-induced β-cell toxicity. Mitochondria are cholesterol-poor organelles, and thus are highly sensitive to even small increases in cholesterol content. Steroidogenic acute regulatory protein (StAR) and the closely related STARD3 protein mediate cholesterol transport to mitochondria. We show that both StAR and STARD3 are upregulated in statin- treated islets. In β cells, StAR overexpression results in mitochondrial cholesterol accumulation, impaired insulin release and reduced cell viability. Also, our data suggest β cells have limited capacity to metabolize cholesterol since they express only two of the cytochrome P450 enzymes known to initiate cholesterol metabolism. Of these, only CYP27A1 is downregulated in islets exposed to statins, and this is accompanied by an increase in miRNA-204, which can suppress CYP27A1 mRNA. We find that lack of islet CYP27A1 per se promotes mitochondrial cholesterol accumulation and impaired insulin secretion. Also, we show stimulating mitophagy to clear cholesterol-laden mitochondria in statin-treated islets protects against β-cell dysfunction. Based on our data, we hypothesize that statin-induced aberrations in cholesterol transport and metabolism lead to mitochondrial cholesterol accumulation, mitochondrial dysfunction, impaired insulin release and β-cell death. The following specific aims will address our hypothesis: Aim 1: To determine the contributions of transport of cholesterol to mitochondria, its subsequent metabolism, or clearance of cholesterol-laden mitochondria to statin-induced β-cell dysfunction/death. Aim 2: To determine whether reducing StAR and/or increasing CYP27A1 expression ameliorates the detrimental effects of statins on β-cell function and mass in vivo. Aim 3: To identify miRs that mitigate statin-induced dysregulation of cholesterol transport and metabolism genes in human islets. This research is innovative and significant, as investigating mitochondrial cholesterol accumulation and miRNAs in statin-induced β-cell dysfunction/death will inform strategies to mitigate the risk of developing T2D.

项目摘要/摘要 他汀类药物是最常用的降胆固醇药物；然而，他汀类药物增加了 新发2型糖尿病(T2D)。虽然这种增加的风险包括他汀类药物损害胰岛β的直接影响- 在细胞功能方面，其潜在机制尚不清楚。随着他汀类药物在美国成年人中的使用趋势， 迫切需要更好地了解他汀类药物是如何导致β细胞死亡的-这一知识将告诉我们 旨在减少接受他汀类药物治疗的患者进展为T2D的策略。为此，我们已经产生了 数据显示，他汀类药物促进线粒体胆固醇积累的作用此前不为人知 在小岛上。令人惊讶的是，几乎没有关于线粒体胆固醇调节机制的文献。 β单元格中的内容。这一知识差距将在拟议的研究中得到解决，这些研究的重点是 他汀类药物诱导的β细胞毒性中胆固醇向线粒体的运输及其随后的代谢。 线粒体是缺乏胆固醇的细胞器，因此对胆固醇的微小增加都高度敏感。 胆固醇含量。类固醇合成急性调节蛋白(STAR)及其密切相关的STARD3蛋白 调节胆固醇向线粒体的运输。我们发现STAR和STARD3都在他汀类药物中上调- 治疗过的胰岛。在β细胞中，STAR过表达导致线粒体胆固醇积聚，受损 胰岛素的释放和细胞活力的降低。此外，我们的数据表明β细胞代谢能力有限 胆固醇，因为它们只表达两种已知的启动胆固醇的细胞色素P450酶 新陈代谢。在这些中，只有CYP27A1在暴露于他汀类药物的胰岛中下调，并且伴随着 MiRNA-204表达增加，可抑制细胞色素P27A1基因的表达。我们发现缺乏胰岛细胞色素P27A1本身 促进线粒体胆固醇积聚和胰岛素分泌受损。此外，我们还展示了激动人心的 在他汀类药物治疗的胰岛中，通过吞噬有丝分裂来清除充满胆固醇的线粒体可以保护β细胞免受功能障碍的影响。 根据我们的数据，我们假设他汀类药物在胆固醇运输和代谢中诱导了异常 导致线粒体胆固醇积聚、线粒体功能障碍、胰岛素释放受损和β细胞 死亡。以下具体目标将解决我们的假设： 目的1：确定胆固醇对线粒体运输的贡献，以及随后的代谢， 或清除富含胆固醇的线粒体，从而导致他汀类药物诱导的β细胞功能障碍/死亡。 目的2：确定降低STAR和/或增加CYP27A1的表达是否能改善 他汀类药物对体内β细胞功能和质量的不利影响。 目的3：确定可减轻他汀类药物诱导的胆固醇转运和代谢失调的MIR 人类胰岛中的基因。 这项研究具有创新性和重要意义，因为研究线粒体胆固醇积累和 他汀类药物诱导的β细胞功能障碍/死亡中的miRNA将为降低发生T2D的风险的策略提供信息。