Kwon Deug-Nam, Choi Yun-Jung, Cho Ssang-Goo, Park Chankyu, Seo Han Geuk, Song Hyuk, Kim Jin-Hoi
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Biomed Res Int. 2015;2015:830315. doi: 10.1155/2015/830315. Epub 2015 Oct 19.
The purpose of this study was to identify the modification/turnover of gene products that are altered in humans due to evolutionary loss of Neu5Gc. CMP-Neu5Ac hydroxylase- (Cmah-) deficient mice show the infiltration of Kupffer cells within liver sinusoids, whereas body and liver weight develop normally. Pathway analysis by use of Illumina MouseRef-8 v2 Expression BeadChip provided evidence that a number of biological pathways, including the glycolysis, gluconeogenesis, TCA cycle, and pentose phosphate pathways, as well as glycogen metabolism-related gene expression, were significantly upregulated in Cmah-null mice. The intracellular glucose supply in Cmah-null mice resulted in mitochondrial dysfunction, oxidative stress, and the advanced glycation end products accumulation that could further induce oxidative stress. Finally, low sirtuin-1 and sirtuin-3 gene expressions due to higher NADH/NAD in Cmah-null mice decreased Foxo-1 and MnSOD gene expression, suggesting that oxidative stress may result in mitochondrial dysfunction in Cmah-null mouse. The present study suggests that mice with CMAH deficiency can be taken as an important model for studying metabolic disorders in humans.
本研究的目的是确定由于Neu5Gc的进化性缺失而在人类中发生改变的基因产物的修饰/周转情况。CMP - Neu5Ac羟化酶（Cmah）缺陷型小鼠在肝血窦内出现库普弗细胞浸润，而其体重和肝脏重量发育正常。使用Illumina MouseRef - 8 v2表达微珠芯片进行的通路分析表明，包括糖酵解、糖异生、三羧酸循环和磷酸戊糖途径以及糖原代谢相关基因表达在内的许多生物学通路在Cmah基因敲除小鼠中显著上调。Cmah基因敲除小鼠细胞内的葡萄糖供应导致线粒体功能障碍、氧化应激以及晚期糖基化终产物积累，而这又会进一步诱导氧化应激。最后，由于Cmah基因敲除小鼠中较高的NADH/NAD导致低水平的沉默信息调节因子1和沉默信息调节因子3基因表达，从而降低了Foxo - 1和锰超氧化物歧化酶基因表达，这表明氧化应激可能导致Cmah基因敲除小鼠出现线粒体功能障碍。本研究表明，Cmah缺陷型小鼠可作为研究人类代谢紊乱的重要模型。
