Department of Science and Environment, Roskilde University, Roskilde, Denmark.
Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Sydney, New South Wales, Australia.
Am J Physiol Cell Physiol. 2022 Aug 1;323(2):C367-C377. doi: 10.1152/ajpcell.00051.2022. Epub 2022 Jun 15.
The microRNA-29 family members miR-29a-3p, miR-29b-3p, and miR-29c-3p are ubiquitously expressed and consistently increased in various tissues and cell types in conditions of metabolic disease, obesity, insulin resistance, and type 2 diabetes. In pancreatic β cells, miR-29a is required for normal exocytosis, but increased levels are associated with impaired β-cell function. Similarly, in liver, miR-29 species are higher in models of insulin resistance and type 2 diabetes, and either knock-out or depletion using a microRNA inhibitor improves hepatic insulin resistance. In skeletal muscle, miR-29 family upregulation is associated with insulin resistance and altered substrate oxidation, and similarly, in adipocytes, overexpression of miR-29a leads to insulin resistance. Blocking miR-29a using nucleic acid antisense therapeutics show promising results in preclinical animal models of obesity and type 2 diabetes, although the widespread expression pattern of miR-29 family members complicates the exploration of single target tissues. However, in fibrotic diseases, such as in late complications of diabetes and metabolic disease (diabetic kidney disease, nonalcoholic steatohepatitis), miR-29 species expression is suppressed by TGF-β allowing increased extracellular matrix collagen to form. In the clinical setting, circulating levels of miR-29a and miR-29b are consistently increased in type 2 diabetes and in gestational diabetes and are also possible prognostic markers for deterioration of glucose tolerance. In conclusion, miR-29 family miRNAs play an essential role in various organs relevant to intermediary metabolism and its upregulation contributes to impaired glucose metabolism, whereas it suppresses fibrosis development. Thus, a correct balance of levels of miR-29 family miRNA seems important for cellular and organ homeostasis in metabolism.
miR-29 家族成员 miR-29a-3p、miR-29b-3p 和 miR-29c-3p 在代谢疾病、肥胖、胰岛素抵抗和 2 型糖尿病等各种组织和细胞类型中普遍表达，并持续升高。在胰腺 β 细胞中，miR-29a 是正常胞吐所必需的，但高水平与 β 细胞功能受损有关。同样，在肝脏中，胰岛素抵抗和 2 型糖尿病模型中 miR-29 种类较高，使用 microRNA 抑制剂进行敲除或耗尽均可改善肝脏胰岛素抵抗。在骨骼肌中，miR-29 家族的上调与胰岛素抵抗和底物氧化改变有关，同样，在脂肪细胞中，miR-29a 的过表达导致胰岛素抵抗。使用核酸反义治疗剂阻断 miR-29a 在肥胖和 2 型糖尿病的临床前动物模型中显示出有前景的结果，尽管 miR-29 家族成员的广泛表达模式使单个靶组织的探索变得复杂。然而，在纤维化疾病中，如糖尿病和代谢疾病的晚期并发症（糖尿病肾病、非酒精性脂肪性肝炎），TGF-β 抑制 miR-29 种类的表达，从而允许更多的细胞外基质胶原形成。在临床环境中，2 型糖尿病和妊娠期糖尿病患者的循环 miR-29a 和 miR-29b 水平持续升高，也是葡萄糖耐量恶化的可能预后标志物。总之，miR-29 家族 miRNA 在与中间代谢相关的各种器官中发挥着重要作用，其上调导致葡萄糖代谢受损，而抑制纤维化的发展。因此，miR-29 家族 miRNA 的水平似乎对代谢过程中的细胞和器官稳态很重要。
