Dhayal S, Welters H J, Morgan N G
Institute of Biomedical and Clinical Science, Peninsula Medical School, Plymouth, UK.
Br J Pharmacol. 2008 Apr;153(8):1718-27. doi: 10.1038/bjp.2008.43. Epub 2008 Feb 25.
Exposure of pancreatic beta-cells to long-chain free fatty acids leads to differential responses according to the chain length and degree of unsaturation. In particular, long-chain saturated molecules such as palmitate (C16:0) cause apoptosis, whereas equivalent mono-unsaturated species (for example, palmitoleate (C16:1)) are not overtly toxic. Moreover, mono-unsaturates exert a powerful cytoprotective response against a range of proapoptotic stimuli. However, the structural requirements that determine cytoprotection have not been determined and form the basis of the present study.
BRIN-BD11 and INS-1 beta-cells were exposed either to the saturated fatty acid palmitate, or to serum withdrawal, to mediate cytotoxicity. The protective effects of a wide range of mono-unsaturated fatty acid derivatives were tested in cytotoxicity assays. Effector caspase activity was also measured and correlated with viability.
The cytotoxic actions of palmitate were inhibited dose-dependently by long-chain mono-unsaturated fatty acids with a defined potency order C18:1>C16:1>>C14:1. The configuration of the double bond was also important with cis forms being more potent than trans forms. Alkylated mono-unsaturated fatty-acid derivates were also cytoprotective, although their efficacy declined as the alkyl chain length increased. Cytoprotection was achieved rapidly on addition of mono-unsaturates and correlated with a rapid and dramatic inhibition of caspase-3/7 activity in palmitate-treated cells.
The data reveal the structural requirements that dictate the cytoprotective actions of mono-unsaturated fatty acids in pancreatic beta-cells. Metabolic activation is not required and the data point at the potential involvement of a fatty acid receptor in mediating cytoprotection.
胰腺β细胞暴露于长链游离脂肪酸时，会根据链长和不饱和度产生不同反应。特别是，长链饱和分子如棕榈酸（C16:0）会导致细胞凋亡，而同等的单不饱和脂肪酸（如棕榈油酸（C16:1））则无明显毒性。此外，单不饱和脂肪酸对一系列促凋亡刺激具有强大的细胞保护作用。然而，决定细胞保护作用的结构要求尚未明确，本研究以此为基础展开。
将BRIN-BD11和INS-1β细胞暴露于饱和脂肪酸棕榈酸或血清饥饿环境中，以介导细胞毒性。在细胞毒性试验中测试了多种单不饱和脂肪酸衍生物的保护作用。还测量了效应半胱天冬酶活性并将其与细胞活力相关联。
棕榈酸的细胞毒性作用受到长链单不饱和脂肪酸的剂量依赖性抑制，其效力顺序为C18:1>C16:1>>C14:1。双键的构型也很重要，顺式比反式更有效。烷基化的单不饱和脂肪酸衍生物也具有细胞保护作用，但其效力会随着烷基链长度的增加而下降。加入单不饱和脂肪酸后能迅速实现细胞保护作用，这与棕榈酸处理的细胞中半胱天冬酶-3/7活性的快速显著抑制相关。
数据揭示了决定单不饱和脂肪酸在胰腺β细胞中细胞保护作用的结构要求。不需要代谢激活，数据表明脂肪酸受体可能参与介导细胞保护作用。
