Morgan Noel G
Institute of Biomedical and Clinical Science, Peninsula Medical School, Plymouth, UK.
Curr Opin Clin Nutr Metab Care. 2009 Mar;12(2):117-22. doi: 10.1097/MCO.0b013e328321e423.
The rising incidence of type 2 diabetes is due, in part, to the detrimental effects of certain fatty acids on pancreatic beta-cell function and viability. The present review examines recent advances in the understanding of the molecular mechanisms by which fatty acids influence the life and death of beta cells.
There are important differences in the cytotoxic potential of fatty acids, with long-chain saturated molecules being the most potent. By contrast, monounsaturates and polyunsaturates are relatively well tolerated and, in some cases, are actively cytoprotective. The mechanisms underlying the toxicity of the saturates may reflect a decrease in protein processing, which drives the accumulation of unfolded proteins in the endoplasmic reticulum. This triggers an apoptotic response by virtue of enhanced endoplasmic reticulum stress and induction of CHOP-10 synthesis. Alterations in the regulatory control of other proapoptotic genes via changes in microRNA synthesis may also contribute. The cytoprotection deriving from incubation with long-chain mono-unsaturates is probably receptor mediated and involves antagonistic actions on the effector arm of the endoplasmic reticulum stress pathway.
The findings have implications for the development of new therapeutic agents designed to minimize beta-cell dysfunction and the loss of beta-cell viability in type 2 diabetes.
2型糖尿病发病率的上升部分归因于某些脂肪酸对胰腺β细胞功能和生存能力的有害影响。本综述探讨了在理解脂肪酸影响β细胞生死的分子机制方面的最新进展。
脂肪酸的细胞毒性潜力存在重要差异，长链饱和分子的毒性最强。相比之下，单不饱和脂肪酸和多不饱和脂肪酸相对易于耐受，在某些情况下还具有积极的细胞保护作用。饱和脂肪酸毒性的潜在机制可能反映出蛋白质加工减少，这导致内质网中未折叠蛋白质的积累。这通过增强内质网应激和诱导CHOP-10合成引发凋亡反应。通过微小RNA合成变化对其他促凋亡基因调控控制的改变也可能起作用。与长链单不饱和脂肪酸孵育产生的细胞保护作用可能是受体介导的，并且涉及对内质网应激途径效应臂的拮抗作用。
这些发现对开发旨在最小化2型糖尿病中β细胞功能障碍和β细胞生存能力丧失的新型治疗药物具有启示意义。
