Hernandez-Vazquez Alain de J, Garcia-Sanchez Josue Andres, Moreno-Arriola Elizabeth, Salvador-Adriano Ana, Ortega-Cuellar Daniel, Velazquez-Arellano Antonio
Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas UNAM - Instituto Nacional de Pediatría, Mexico City, Mexico.
J Nutrigenet Nutrigenomics. 2016;9(5-6):287-299. doi: 10.1159/000456663. Epub 2017 Feb 18.
Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine. They are similar to the ones we have previously found in biotin deficiency, another ATP generation cofactor. Here we show that thiamine deficiency substantially reduced the energy state in the liver and activated the energy sensor AMP-activated kinase. With this vitamin deficiency, several metabolic parameters changed: blood glucose was diminished and serum lactate was increased, but insulin, triglycerides, and cholesterol, as well as liver glycogen, were reduced. These results indicate a severe change in the energy status of the whole organism. Our findings were associated with modified hepatic levels of the mRNAs of several carbon metabolism genes: a reduction of transcripts for liver glucokinase and fatty acid synthase and augmentation of those for carnitine palmitoyl transferase 1 and phosphoenolpyruvate carboxykinase as markers for glycolysis, fatty acid synthesis, beta-oxidation, and gluconeogenesis, respectively. Glucose tolerance was initially increased, suggesting augmented insulin sensitivity, as we had found in biotin deficiency; however, in the case of thiamine, it was diminished from the 3rd week on, when the deficient animals became undernourished, and paralleled the changes in AKT and mTOR, 2 main proteins in the insulin signaling pathway. Since many of the metabolic and gene expression effects on mice deprived of thiamine are similar to those in biotin deficiency, it may be that they result from a more general impairment of oxidative phosphorylation due to a shortage of ATP generation cofactors. These findings may be relevant to energy-related disorders, among them several inborn errors of metabolism, as well as common energy disorders like obesity, diabetes, and neurodegenerative illnesses.
硫胺素是生成三磷酸腺苷（ATP）所需的几种必需辅助因子之一。其缺乏症，如在脚气病和韦尼克 - 科尔萨科夫综合征中，已经被研究了数十年。然而，其在细胞和分子水平上的作用机制仍未完全明确。由于它作为丙酮酸、支链酮酸和酮戊二酸脱氢酶的辅酶，其营养缺乏在一定程度上是先天性代谢缺陷的表型模拟，其中包括枫糖尿症。在本文中，我们报告了硫胺素缺乏小鼠的代谢和基因组学研究结果。这些结果与我们之前在生物素缺乏（另一种ATP生成辅助因子）研究中发现的结果相似。在此我们表明，硫胺素缺乏会显著降低肝脏的能量状态并激活能量传感器AMP激活的蛋白激酶。随着这种维生素缺乏，几个代谢参数发生了变化：血糖降低，血清乳酸增加，但胰岛素、甘油三酯和胆固醇以及肝糖原减少。这些结果表明整个生物体的能量状态发生了严重变化。我们的研究结果与几种碳代谢基因的肝脏mRNA水平改变有关：肝葡萄糖激酶和脂肪酸合酶的转录本减少，而肉碱棕榈酰转移酶1和磷酸烯醇丙酮酸羧激酶的转录本增加，它们分别作为糖酵解、脂肪酸合成、β-氧化和糖异生的标志物。葡萄糖耐量最初增加，表明胰岛素敏感性增强，这与我们在生物素缺乏研究中发现的情况相同；然而，在硫胺素缺乏的情况下，从第3周开始葡萄糖耐量降低，此时缺乏硫胺素的动物开始营养不良，并且与胰岛素信号通路中的2种主要蛋白质AKT和mTOR的变化平行。由于硫胺素缺乏小鼠的许多代谢和基因表达效应与生物素缺乏相似，可能是由于ATP生成辅助因子短缺导致氧化磷酸化更普遍受损所致。这些发现可能与能量相关疾病有关，其中包括几种先天性代谢缺陷以及肥胖、糖尿病和神经退行性疾病等常见能量紊乱。
