PPAR signaling pathway is a key modulator of liver proteome in pups born to vitamin B12 deficient rats
PPAR signaling pathway is a key modulator of liver proteome in pups born to vitamin B12 deficient rats
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DOI：
10.1016/j.jprot.2013.07.027
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发表时间：
2013-10-08
影响因子：
3.3
通讯作者：
Sengupta, Shantanu
中科院分区：
文献类型：
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作者：
Ahmad, Shadab;Kumar, K. Anand;Sengupta, Shantanu
众所周知，母亲在子宫内营养不足可预测后代患心血管疾病、糖尿病和许多神经系统疾病等复杂疾病的风险，维生素B-12就是其中一种重要的微量营养素。在这里，我们进行了2D-DIGE，然后进行MALDI TOF/TOF分析，以鉴定在喂食维生素B-12缺乏饮食的母亲与对照饮食所生的幼崽的肝脏中差异表达的蛋白质。为了进一步确定因果关系，我们分析了分娩时B-12恢复对幼仔蛋白质水平和表型的影响。我们确定了38个差异表达的蛋白质，这些蛋白质在参与氨基酸、脂质和碳水化合物代谢调节的途径中富集。此外，β-氧化途径中的三种酶（羟酰辅酶A脱氢酶、中链特异性酰基辅酶A脱氢酶、3-酮脂酰辅酶A硫解酶）在喂食维生素B-12缺乏饮食的母亲所生的幼崽中下调。我们观察到年龄依赖性差异表达过氧化物酶体增殖物激活受体（PPAR）α和γ缺陷的幼崽。有趣的是，27个差异表达的蛋白质的表达恢复到对照水平后，从分娩的雌性大鼠维生素B-12的康复。因此，我们的研究首次证明了母体维生素B-12缺乏通过调节过氧化物酶体增殖物激活受体信号通路影响幼鼠的脂质和其他微量营养素代谢。生物学意义母体维生素B-12缺乏已被证明可预测下一代成年期复杂疾病如动脉粥样硬化、II型糖尿病等的发生。我们之前已经证明，用缺乏维生素B-12的饮食喂养的雌性大鼠所生的幼崽肥胖，并产生了高水平的其他中间性状，如甘油三酯、胆固醇等，这些性状与糖尿病和心血管疾病的风险有关。在这项工作中，使用差异蛋白质组学方法，我们已经确定了维生素B-12缺乏的幼崽肝脏中代谢过程的改变。我们还证明了参与β-氧化途径的蛋白质被下调。此外，PPARalpha和PPARgamma的差异表达被证明是母体维生素B-12缺乏时脂质、氨基酸和碳水化合物代谢改变的主要调节因子。(C)2013爱思唯尔有限公司版权所有。
Maternal nutritional deficiency in-utero is known to predict risk of complex disorders like cardiovascular disease, diabetes and many neurological disorders in the offspring and vitamin B-12 is one such critical micronutrient. Here we performed 2D-DIGE followed by MALDI TOF/TOF analysis to identify proteins that are differentially expressed in liver of pups born to mothers fed vitamin B-12 deficient diet vis-a-vis control diet. To further establish causality, we analyzed the effect of B-12 rehabilitation at parturition on the protein levels and the phenotype in pups. We identified 38 differentially expressed proteins that were enriched in pathways involved in the regulation of amino acid, lipid and carbohydrate metabolism. Further, three enzymes in the beta-oxidation pathway (hydroxyacyl-coenzyme A dehydrogenase, medium-chain specific acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase) were down-regulated in pups born to mothers fed vitamin B-12 deficient diet. We observed age-dependent differential expression of peroxisome proliferator activated-receptor (PPAR) alpha and gamma in the deficient pups. Interestingly, expression of 27 proteins that were differentially expressed was restored to the control levels after rehabilitation of female rats with vitamin B-12 from parturition. Our study thus provides the first evidence that maternal vitamin B-12 deficiency influences lipid and other micronutrient metabolism in pups through regulation of PPAR signaling pathway.Biological significanceMaternal vitamin B-12 deficiency has been shown to predict the onset of complex disorders like atherosclerosis, type II diabetes etc. in the next generation during their adulthood. We have shown earlier that pups born to female rats fed with vitamin B-12 deficient diet were obese and developed high levels of other intermediate traits such as triglycerides, cholesterol etc. that are related to the risk of diabetes and cardiovascular disorders. In this piece of work using differential proteomic approach we have identified the altered metabolic processes in the liver of vitamin B-12 deficient pups. We have also documented that the proteins involved in beta-oxidation pathway are down-regulated. Further, differential expression of PPAR alpha and PPAR gamma was evidently documented as the master regulator for the alteration of lipid, amino acid and carbohydrate metabolism during maternal vitamin B-12 deficiency. (C) 2013 Elsevier B.V. All rights reserved.