CMP-Neu5Ac Hydroxylase Null Mice as a Model for Studying Metabolic Disorders Caused by the Evolutionary Loss of Neu5Gc in Humans

Figure 6

Molecular mechanisms of glucose-mediated regulation of sirtuins and oxidative stress in Cmah-null mice. (a) Expression of genes involved in glycolysis and glyconeogenesis, confirmed in WT and Cmah-null mouse-derived livers by a pathway-focused glucose metabolism PCR array. (b) Expression levels of genes involved in the molecular mechanisms of sirtuin and oxidative stress regulation were determined by RT-qPCR of RNA samples from liver tissues of WT and Cmah-null mice. Measurements were performed in triplicate, and the calculated mean expression was corrected using Gapdh expression levels. Error bars indicate standard deviations. Significant differences are indicated by and , . (c) Glucose can directly or indirectly affect the main regulators of the aging process and sirtuin activity, as well as other contributors to aging such as oxidative stress. Increased glycolytic activity would tend to provoke an accumulation of NADH and lower the availability of NAD, resulting in decreased sirtuin activity. In addition, activation of the TCA cycle and β-oxidation of fatty acids distribute acetyl-CoA and acyl CoA, respectively, to the mitochondrial OXPHOS pathway. Therefore, lactate produced by glycolysis may be converted to pyruvate and ultimately enter the TCA cycle. Collectively, these results show that, via increased glycolysis, increased intracellular glucose levels can lead to (i) mitochondrial dysfunction and oxidative stress due to continuous ATP synthesis and (ii) accumulation of highly toxic advanced glycation end products (AGEs), which can provoke further oxidative stress. These observations suggest that the evolutionary loss of CMAH function may make humans more prone to diabetes or aging than other mammals.

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