Abstract
Monocarboxylates such as pyruvate, lactate and ketone bodies are crucial for energy supply of all tissues, especially during energy restriction. The transport of monocarboxylates across the plasma membrane of cells is mediated by monocarboxylate transporters (MCTs). Out of 14 known mammalian MCTs, six isoforms have been functionally characterized to transport monocarboxylates and short chain fatty acids (MCT1-4), thyroid hormones (MCT8, -10) and aromatic amino acids (MCT10). Knowledge on the regulation of the different MCT isoforms is rare. In an attempt to get more insights in regulation of MCT expression upon energy deprivation, we carried out a comprehensive analysis of tissue specific expression of five MCT isoforms upon 48 h of fasting in mice. Due to the crucial role of peroxisome proliferator-activated receptor (PPAR)-α as a central regulator of energy metabolism and as known regulator of MCT1 expression, we included both wildtype (WT) and PPARα knockout (KO) mice in our study. Liver, kidney, heart, small intestine, hypothalamus, pituitary gland and thyroid gland of the mice were analyzed. Here we show that the expression of all examined MCT isoforms was markedly altered by fasting compared to feeding. Expression of MCT1, MCT2 and MCT10 was either increased or decreased by fasting dependent on the analyzed tissue. MCT4 and MCT8 were down-regulated by fasting in all examined tissues. However, PPARα appeared to have a minor impact on MCT isoform regulation. Due to the fundamental role of MCTs in transport of energy providing metabolites and hormones involved in the regulation of energy homeostasis, we assumed that the observed fasting-induced adaptations of MCT expression seem to ensure an adequate energy supply of tissues during the fasting state. Since, MCT isoforms 1–4 are also necessary for the cellular uptake of drugs, the fasting-induced modifications of MCT expression have to be considered in future clinical care algorithms.
Highlights
Monocarboxylates such as pyruvate, lactate and ketone bodies are central players in the metabolism of carbohydrates, lipids and amino acids and crucial for energy supply of all tissues, especially during food shortage
Fasted WT and PPARa KO mice were characterized by higher plasma concentrations of non-esterified fatty acids (NEFA) than fed mice of the same genotype, whereby the highest NEFA concentrations were observed in fasted PPARa KO mice (Figure 1A)
These transport processes as well as transport of thyroid hormones and aromatic amino acids are mediated by members of the monocarboxylate transporters (MCTs) family
Summary
Monocarboxylates such as pyruvate, lactate and ketone bodies are central players in the metabolism of carbohydrates, lipids and amino acids and crucial for energy supply of all tissues, especially during food shortage. MCT isoforms 1–4 vary in tissue and subcellular distribution and differ in their substrate specificity [1]. This allows shuttling of the substrates from tissues where they are produced to tissues that use them for oxidation or gluconeogenesis. MCT8 is a specific thyroid hormone transporter [17]. MCT10, referred to as TAT1, transports aromatic amino acid residues [19] and was recently found to transport thyroid hormones [20,21]. Studies indicate that isoforms MCT1-4 are regulated at both transcriptional and post-transcriptional level [2]. Their expression can be modulated by substances like e.g. noradrenaline, insulin, IGF-1, butyrate or by other regulatory factors like exercise, hypoxia or the diabetic state. PPARa is a lipid-activated nuclear receptor that acts as a nutritional state sensor in mammalian cells and mediates the adaptive response to fasting by inducing fatty acid oxidation and ketogenesis [32,33]
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