Selective LXR agonist DMHCA corrects retinal and bone marrow dysfunction in type 2 diabetes.
Selective LXR agonist DMHCA corrects retinal and bone marrow dysfunction in type 2 diabetes.
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DOI：
10.1172/jci.insight.137230
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发表时间：
2020-07
期刊：
影响因子：
8
通讯作者：
Cristiano P. Vieira;Seth D Fortmann;Masroor Hossain;A. L. Longhini;Sandra S. Hammer;Bright Asare-Bediako;D. Crossman;M. S. Sielski;Yvonne Adu-Agyeiwaah;Mariana Dupont;J. Floyd;S. Li Calzi;Todd A. Lydic;R. Welner;G. Blanchard;J. Busik;M. Grant
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文献类型：
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作者：
Cristiano P. Vieira;Seth D Fortmann;Masroor Hossain;A. L. Longhini;Sandra S. Hammer;Bright Asare-Bediako;D. Crossman;M. S. Sielski;Yvonne Adu-Agyeiwaah;Mariana Dupont;J. Floyd;S. Li Calzi;Todd A. Lydic;R. Welner;G. Blanchard;J. Busik;M. Grant
在糖尿病血脂异常中，胆固醇在质膜上积聚，降低流动性，从而抑制细胞转导配体激活的信号通路的能力。肝X受体(LXRs)是调节细胞内胆固醇的主要细胞机制，在炎症和疾病发病机制中发挥重要作用。N，N-二甲基-3-羟基胆碱胺(β)是一种选择性低密度脂蛋白受体激动剂，它特异性地激活低密度脂蛋白受体途径的胆固醇外排臂，而不刺激甘油三酯的合成。在这项研究中，我们使用多系统的方法来了解DMHCA对2型糖尿病(db/db)小鼠和人类循环血管生成细胞(CACs)的治疗效果和分子机制，这两种细胞是具有血管修复能力的造血祖细胞。我们发现，DMHCA足以纠正糖尿病患者的视网膜和骨髓功能障碍，从而恢复视网膜结构、功能和胆固醇的动态平衡；恢复CACs的膜流动性；阻碍全身炎症；纠正骨髓病理。通过对未经治疗和DMHCA治疗的糖尿病小鼠的Lineage-SCA1+c-Kit+(LSK)造血干细胞(HSCs)进行单细胞RNA测序，我们为造血提供了潜在的新见解，并揭示了DMHCA通过减少髓样病变和增加CACs和红细胞祖细胞来纠正糖尿病HSCs的作用机制。综上所述，这些发现证明了DMHCA治疗对糖尿病引起的视网膜和BM病理的有益影响。
In diabetic dyslipidemia, cholesterol accumulates in the plasma membrane, decreasing fluidity and thereby suppressing the ability of cells to transduce ligand-activated signaling pathways. Liver X receptors (LXRs) make up the main cellular mechanism by which intracellular cholesterol is regulated and play important roles in inflammation and disease pathogenesis. N, N-dimethyl-3β-hydroxy-cholenamide (DMHCA), a selective LXR agonist, specifically activates the cholesterol efflux arm of the LXR pathway without stimulating triglyceride synthesis. In this study, we use a multisystem approach to understand the effects and molecular mechanisms of DMHCA treatment in type 2 diabetic (db/db) mice and human circulating angiogenic cells (CACs), which are hematopoietic progenitor cells with vascular reparative capacity. We found that DMHCA is sufficient to correct retinal and BM dysfunction in diabetes, thereby restoring retinal structure, function, and cholesterol homeostasis; rejuvenating membrane fluidity in CACs; hampering systemic inflammation; and correcting BM pathology. Using single-cell RNA sequencing on lineage-sca1+c-Kit+ (LSK) hematopoietic stem cells (HSCs) from untreated and DMHCA-treated diabetic mice, we provide potentially novel insights into hematopoiesis and reveal DMHCA's mechanism of action in correcting diabetic HSCs by reducing myeloidosis and increasing CACs and erythrocyte progenitors. Taken together, these findings demonstrate the beneficial effects of DMHCA treatment on diabetes-induced retinal and BM pathology.