PDF(Pubmed)
Abstract：
Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p < 0.0001), and in the bran, decreased 8-isoprostane amounts (p < 0.0001), increased resolvin D1 levels (p < 0.005) and increased quantity of total n-3 PUFAs (p < 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = -0.562, p = 0.0001), resolvin D1 (r = 0.712, p < 0.0001), and 8-isoprostane brain levels (r = -0.690, p < 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.
摘要：
脂肪酸氧化的脂质介质已被证明与Krabbe病（KD）的严重程度有关，与半乳糖基神经酰胺酶（GALC）基因突变有关的疾病。本研究旨在使用Twitcher（Tw）动物作为KD的自然模型，研究补充n-3多不饱和脂肪酸（PUFA）对KD性状和脂肪酸代谢的影响。野生型(Wt),杂合（Ht），和受影响的Tw动物在10至35天的生命中用36mgn-3PUFA/kg体重/天口服治疗。PUFA过氧化的最终产物（8-异前列腺素），参与炎性渗出物消退的脂质介质（消退素D1），并分析小鼠脑中n-3PUFA的总量。在两只老鼠中，补充n-3PUFA可延迟疾病症状的表现（p<0.0001），在麸皮中，8-异前列腺素含量降低（p<0.0001），消退素D1水平增加(p<0.005)，n-3PUFA总量增加(p<0.05)。此外，全脑n-3PUFA水平与疾病严重程度相关（r=-0.562，p=0.0001），分辨率D1（r=0.712，p<0.0001），和8-异前列腺素脑水平（r=-0.690，p<0.0001）。第一次在KD的自然模型中，显示n-3PUFA的脑水平决定疾病的严重程度，并参与脑PUFA的过氧化作用以及促分辨脂质介质的产生。还显示，饮食中补充n-3PUFA会导致疾病的表型呈现减慢和脂质介质产生的恢复。
