Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V. (DZD e.V.), Neuherberg, Germany.
Eternygen GmbH, Berlin, Germany.
Pharmacol Ther. 2018 May;185:1-11. doi: 10.1016/j.pharmthera.2017.10.003. Epub 2017 Oct 5.
The regulation of metabolic processes by the Indy (I'm Not Dead Yet) (SLC13A5/NaCT) gene was revealed through studies in Drosophila melanogaster and Caenorhabditis elegans. Reducing the expression of Indy in these species extended their life span by a mechanism resembling caloric restriction, without reducing food intake. In D. melanogaster, mutating the Indy gene reduced body fat content, insulin-like proteins and reactive oxygen species production. Subsequent studies indicated that Indy encodes a citrate transporter located on the cell plasma membrane. The transporter is highly expressed in the mammalian liver. We generated a mammalian knock out model deleting the mammalian homolog mIndy (SLC13A5). The knock out animals were protected from HFD induced obesity, fatty liver and insulin resistance. Moreover, we have shown that inducible and liver selective knock down of mIndy protects against the development of fatty liver and insulin resistance and that obese humans with type 2 diabetes and non-alcoholic fatty liver disease have increased levels of mIndy. Therefore, the transporter mINDY (NaCT) has been proposed to be an 'ideal target for the treatment of metabolic disease'. A small molecule inhibitor of the mINDY transporter has been generated, normalizing glucose levels and reducing fatty liver in a model of diet induced obese mice. Taken together, studies from lower organisms, mammals and humans suggest that mINDY (NaCT) is an attractive target for the treatment of metabolic disease.
Indy（我还没死）（SLC13A5/NaCT）基因通过对黑腹果蝇和秀丽隐杆线虫的研究，调节代谢过程。通过降低这些物种中 Indy 的表达，其寿命延长了，其机制类似于热量限制，但不会减少食物摄入。在黑腹果蝇中，Indy 基因突变降低了体脂肪含量、胰岛素样蛋白和活性氧的产生。随后的研究表明，Indy 编码一种位于细胞膜上的柠檬酸转运蛋白。该转运蛋白在哺乳动物肝脏中高度表达。我们构建了一种哺乳动物 Indy 基因敲除模型（mIndy，SLC13A5）。该敲除动物对高脂饮食诱导的肥胖、脂肪肝和胰岛素抵抗具有保护作用。此外，我们还表明，mIndy 的诱导性和肝脏选择性敲低可预防脂肪肝和胰岛素抵抗的发展，并且患有 2 型糖尿病和非酒精性脂肪性肝病的肥胖人群中 mIndy 水平升高。因此，该转运蛋白 mINDY（NaCT）被提议为“代谢性疾病治疗的理想靶点”。已经生成了 mINDY 转运蛋白的小分子抑制剂，可使饮食诱导肥胖小鼠的血糖水平正常化并减少脂肪肝。综上所述，来自低等生物、哺乳动物和人类的研究表明，mINDY（NaCT）是治疗代谢性疾病的有吸引力的靶点。
