ABSTRACT
Biotin is the prosthetic group of carboxylases that have important roles in the metabolism of glucose, fatty acids and amino acids. Biotinidase has a key role in the reutilization of the biotin, catalyzing the hydrolysis of biocytin (ε-N-biotinyl-l-lysine) and biocytin-containing peptides derived from carboxylase turnover, thus contributing substantially to the bioavailability of this vitamin. Deficient activity of biotinidase causes late-onset multiple carboxylase in humans, whose pathogenic mechanisms are poorly understood. Here we show that a knock-out biotinidase-deficient mouse from a C57BL/6 background that was fed a low biotin diet develops severe ATP deficit with activation of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK), inhibition of the signaling protein mTOR, driver of protein synthesis and growth, and affecting the expression of central-carbon metabolism genes. In addition, sensitivity to insulin is augmented. These changes are similar to those observed in nutritionally biotin-starved rats. These findings further our understanding of the pathogenesis of human biotinidase deficiency.
Subject(s)
Biotinidase Deficiency/genetics , Biotinidase Deficiency/metabolism , Carbon , Energy Metabolism , Gene Expression , Animals , Biotin/deficiency , Biotin/metabolism , Biotinidase Deficiency/diet therapy , Blood Glucose , Body Weight , Carbon/metabolism , Carnitine/analogs & derivatives , Carnitine/metabolism , Diet , Disease Models, Animal , Energy Metabolism/genetics , Humans , Liver/metabolism , Mice , Mice, Knockout , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
BACKGROUND/AIM: Biotin affects the genetic expression of several glucose metabolism enzymes, besides being a cofactor of carboxylases. To explore how extensively biotin affects the expression of carbon metabolism genes, we studied the effects of biotin starvation and replenishment in 3 distantly related eukaryotes: yeast Saccharomyces cerevisiae, nematode Caenorhabditis elegans and rat Rattus norvegicus. METHODS: Biotin starvation was produced in Wistar rats, in C. elegans N2 and S. cerevisiae W303A fed with abundant glucose. High-density oligonucleotide microarrays were used to find gene expression changes. Glucose consumption, lactate and ethanol were measured by conventional tests. RESULTS: In spite of abundant glucose provision, the expression of fatty oxidation and gluconeogenic genes was augmented, and the transcripts for glucose utilization and lipogenesis were diminished in biotin starvation. These results were associated with diminished glucose consumption and glycolysis products (lactate and ethanol in yeast), which was consistent across 3 very different eukaryotes. CONCLUSION: The results point toward a strongly selected role of biotin in the control of carbon metabolism, and in adaptations to variable availability of carbon, conceivably mediated by signal transduction including soluble guanylate cyclase, cGMP and a cGMP-dependent protein kinase (PKG) and/or biotin-dependent processes.
