Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute (BK-21), Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Free Radic Biol Med. 2010 Nov 30;49(10):1522-33. doi: 10.1016/j.freeradbiomed.2010.08.015. Epub 2010 Aug 19.
Carbonyl reductase 1 (CBR1) plays an important role in the detoxification of reactive lipid aldehydes. Oxidative stress has been implicated in the pathogenesis of pancreatic β-cell failure. However, the functional role of CBR1 in pancreatic β-cell failure has not been studied yet. Therefore, we investigated the role of CBR1 in pancreatic β-cell failure under glucotoxic and glucolipotoxic conditions. Under both conditions, knockdown of CBR1 by specific siRNA increased β-cell apoptosis, expression of lipogenic enzymes (such as ACC, FAS, and ABCA1), intracellular lipid accumulation, oxidative stress, ER stress, and nuclear SREBP1c, but decreased glucose-stimulated insulin secretion. In contrast, overexpression of CBR1 showed the opposite effects. The antioxidants N-acetyl-l-cysteine and Tiron, as well as the FAS inhibitor cerulenin, reversed the effects of CBR1 knockdown. Interestingly, the expression level and enzyme activity of CBR1 were significantly decreased in pancreatic islets of db/db mice, compared with those of wild-type mice. In conclusion, CBR1 protects pancreatic β-cells against oxidative stress and promotes their survival in glucotoxicity and glucolipotoxicity.
羰基还原酶 1（CBR1）在活性脂质醛的解毒中发挥重要作用。氧化应激与胰腺β细胞衰竭的发病机制有关。然而，CBR1 在胰腺β细胞衰竭中的功能作用尚未得到研究。因此，我们研究了 CBR1 在糖毒性和糖脂毒性条件下对胰腺β细胞衰竭的作用。在这两种情况下，通过特异性 siRNA 敲低 CBR1 都会增加β细胞凋亡、脂生成酶（如 ACC、FAS 和 ABCA1）的表达、细胞内脂质积累、氧化应激、内质网应激和核 SREBP1c，但会降低葡萄糖刺激的胰岛素分泌。相比之下，过表达 CBR1 则显示出相反的效果。抗氧化剂 N-乙酰-l-半胱氨酸和 Tiron 以及 FAS 抑制剂 cerulenin 逆转了 CBR1 敲低的作用。有趣的是，与野生型小鼠相比，db/db 小鼠的胰岛中 CBR1 的表达水平和酶活性显著降低。总之，CBR1 可保护胰腺β细胞免受氧化应激，并促进其在糖毒性和糖脂毒性中的存活。
