Thiamine Deprivation Produces a Liver ATP Deficit and Metabolic and Genomic Effects in Mice: Findings Are Parallel to Those of Biotin Deficiency and Have Implications for Energy Disorders

Abstract

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.

Thiamine deficiency affects glucose transport and β‐oxidation in rats

“…Thiamine deficiency (TD) causes besides the weight loss, also disorders of nervous system and cardiomyopathy (Hoffman., ; Krasicka, Gralak, Sieranska, & Kulasek, ). It may decrease the membrane conductance, cause disorders in ATP production (Oliveira, Galan, Ribeiro, & Santos Cruz, ), brain failures (Aikawa et al, ; Ke, DeGiorgio, Volpe, & Gibson, ; Yu et al, ) and liver disorders (Hernandez‐Vazquez et al, ). Moreover, the TD may result in an increase of the frequency of death of cardiac cells (Zangen & Shainberg, ).…”

“…and liver disorders (Hernandez-Vazquez et al, 2016). Moreover, the TD may result in an increase of the frequency of death of cardiac cells (Zangen & Shainberg, 1997).…”

All You Can Feed: Some Comments on Production of Mouse Diets Used in Biomedical Research with Special Emphasis on Non-Alcoholic Fatty Liver Disease Research

“…Growth retardation and malfunction of reproductive organs and ovulation; congenital debility of young animals with loss of both equilibrium and coordination [109,110] Zinc Reduced immune responses after challenging with pathogen indicated by greater weight loss, stool shedding, mucus production and diarrhea [111] Iodine Development of carcinoma of the thyroid; formation of oxidative stress and DNA modifications [112,113] Selenium Potentiate the development of autoantibodies; reduction of amino acid levels and elevation of mononucleotides resulting in dysregulated metabolomes and age-associated decline of protein synthesis; development of widespread pyogranulomas [114][115][116] Thiamine Reduction of energy state in the liver; reduction of blood glucose, insulin, triglycerides, cholesterol, liver glycogen; increase of serum lactate [117] Biotin Impairment of mitochondrial structure and function; intoxication with propionyl-CoA; systemic inflammation [118] Vitamin D…”

Mito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins

“…Pyruvate has been suggested to bind to EGLNs catalytic site, thereby inhibiting EGLN activity and stabilizing HIF1A (Lu et al, 2005). Since vitamin B1 (thiamine) is essential for enzymatic activity of PDH and OGDH, thiamine deficiency decreases the activities of both PDH and OGDH (Figure 3), which is clinically characterized by increased plasma levels of pyruvate and lactate (Frohman and Day, 1949; Park and Gubler, 1969; Falder et al, 2010; Sweet and Zastre, 2013; Hernandez-Vazquez et al, 2016). The elevated pyruvate levels observed in B1 deficiency could impact HIF1 signaling.…”