| First Author | Chen Y | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100624 | PubMed ID | 33812996 |
| Mgi Jnum | J:316228 | Mgi Id | MGI:6707272 |
| Doi | 10.1016/j.jbc.2021.100624 | Citation | Chen Y, et al. (2021) NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity. J Biol Chem :100624 |
| abstractText | The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased non-esterified fatty acid (NEFA) and triglyceride (TG) in liver and plasma, and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in liver and circulation, and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKalpha1-dependent phosphorylation of AKT and GSK3beta. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment. |
