Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
复制标题
中性氨基酸转运蛋白SLC7A10在脂肪细胞脂肪储存、肥胖和胰岛素抵抗中的作用
DOI：
10.2337/db20-0096
复制
发表时间：
2021-03-01
期刊：
影响因子：
7.7
通讯作者：
Dankel, Simon N.
中科院分区：
文献类型：
--
作者：
Jersin, Regine A.;Tallapragada, Divya Sri Priyanka;Dankel, Simon N.
阐明控制脂质储存、氧化应激和胰岛素抵抗的机制可能会改善2型糖尿病和其他肥胖相关疾病的治疗选择。在这里，我们发现，脂肪表达的小中性氨基酸转运蛋白SLC 7A 10，也被称为丙氨酸-丝氨酸-半胱氨酸转运蛋白-1（ASC-1），显示出强烈的负相关内脏肥胖，胰岛素抵抗，脂肪细胞肥大在多个队列。一致地，在斑马鱼体内Slc 7a 10功能的丧失加速饮食诱导的体重增加和脂肪细胞增大。在机制上，人和鼠脂肪细胞中的SLC 7A 10抑制降低脂肪细胞丝氨酸摄取和总谷胱甘肽水平，并促进活性氧（ROS）产生。相反，SLC 7A 10过表达减少ROS产生并增加线粒体呼吸能力。RNA测序显示，在SLC 7A 10缺失后，人脂肪细胞和斑马鱼内脏脂肪组织之间的基因表达发生了一致的变化，例如，SCD（脂质储存）上调和CPT 1A（脂质氧化）下调。有趣的是，ROS清除剂减少了脂质积累并减弱了SLC 7A 10抑制的脂质储存效应。这些数据揭示了脂肪细胞SLC 7A 10作为脂肪细胞对营养和氧化应激的恢复力的一种新的重要调节剂，部分通过提高谷胱甘肽水平和线粒体呼吸，有助于减少ROS生成，脂质积累，脂肪细胞肥大，胰岛素抵抗和2型糖尿病。
Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.