Intensified expressions of a monocarboxylate transporter in consistently renewing tissues of the mouse

Abstract

Monocarboxylates-lactate and ketone bodies-can compensate for glucose as energy sources under certain physical conditions. To identify the main energy source used in self-renewing tissues, expression profiles of monocarboxylate transporters (MCTs) were mainly investigated immunohistochemically in the gastrointestinal tract, skin, and bone marrow of mice, with reference to glucose transporters. In the small intestine, MCT1-immunoreactive epithelial cells accumulated in crypts with a selective immunolabeling along the basolateral membrane of cells. BrdU-labeled dividing cells were included in the cryptal MCT1-immunoreactive foci. The skin displayed an intense and extensive immunoreactivity for MCT1 in the hair bulge, which gives rise to the epidermis, hair, and sebaceous gland. The stratified squamous epithelium in the esophagus contained MCT1-immunoreactive cells in the basal layer but frequently lacked GLUT1-immunoreactive cells. The bone marrow was largely immunoreactive for MCT1 but not for GLUT1, suggesting the active production and utilization of monocarboxylates for hematopoiesis under hypoxic conditions. These findings support the idea that monocarboxylates are favorite energy sources in self-renewing tissues.Mammals use two kinds of energy substrates, glucose and monocarboxylates. The latter includes lactate, acetate, ketone bodies, and others. These monocarboxylates, which are intermediate metabolites, provide a "ready-to-use" fuel in most cells or are converted into glucose (gluconeogenesis) and fatty acids (lipogenesis). They can compensate for glucose as an energy source under several physical conditions such as fasting, diabetes, and the neonatal period (16,35). The production of monocarboxylates does not need oxygen; therefore, they may be evolutionally older (more primitive) energy substrates than glucose, since the concentration of O 2 was low in ancient times. Hypoxic conditions exist in the bone marrow and tumors where proliferative activities are high, and some signals of hypoxia stimulate the cell proliferation (7, 9). There is a possibility that the monocarboxylates produced by anaerobic glycolysis are favorite energy sources for cell growth in selfrenewing tissues and tumors. In mammals, a membrane-bound transporter family mediates the uptake and excretion of monocarboxylates. A representative transporter for monocarboxylates is the monocarboxylate transporter (MCT) and the classified SLC16 gene family. MCT is a H + -coupled, electroneutral, and bi-directional transporter composed of twelve transmembrane domains with intracellular N and C terminal domains (10, 11). To date, fourteen MCT isoforms-each having a unique distribution and different sequence homology-have been identified in mammals, though only four (MCT1-MCT4) have been demonstrated experimentally to facilitate the proton-linked transport of metabolically important monocarboxylates (14,23). It is possible to evaluate the existence of a monocarbox-

<b>Cellular distributions of monocarboxylate transporters: a r</b><b>eview </b>

“…Similar to tumor cells, normally proliferating cells may prefer to use monocarboxylates rather than glucose. In the small intestine, crypts largely consisting of proliferating and immature cells express MCT1 more intensely, especially the dividing cells (144). A similarly intensified expression of MCT1 is found at the proliferating zone of the stomach and at the basal layer of the esophagus.…”

“…The MCT1 antibody more intensely labels the plasma membrane of immature red blood cells containing a nucleus, as seen in the bone marrow and placenta of the mouse. It is noteworthy that the bone marrow displays an intense expression of MCT1, in contrast to a faint expression of GLUTs (144). The plasma membrane of hematopoietic cells, mainly erythrocytic progenitor cells, is selectively immunolabeled for MCT1 in the murine bone marrow (144).…”

“…The cellular localization along the entire length of the plasma membrane is common between the two transporters. These transporters must supply nutrients derived from the circulation for cell division and proliferation in the epidermis, a representative tissue consistently renewing itself (144). Acetate, lactate, and other monocarboxylates can serve as materials for lipogenesis via acetyl-CoA.…”

“…It is noteworthy that the bone marrow displays an intense expression of MCT1, in contrast to a faint expression of GLUTs (144). The plasma membrane of hematopoietic cells, mainly erythrocytic progenitor cells, is selectively immunolabeled for MCT1 in the murine bone marrow (144). Sustained exercise releases a great amount of lactate into the blood to induce a lactate influx from the plasma to erythrocytes (133).…”

<b>Immunohistochemical localization of GLUT3, MCT1, and MCT2 in the testes of mice and rats: the use of different energy sources in </b><b>spermatogenesis </b>

“…Intermediate metabolites including lactate, acetate, and ketone bodies provide a "ready-to-use" fuel in most cells. These metabolic monocarboxylates are the fundamental energy in some cell types such as neurons (31), oocytes (22), and diving cells (35), and can compensate for glucose as an energy source for most cells under some conditions such as fasting, diabetes, and the neonatal period. For utilization of the monocarboxxylates, cells are provided with specific membrane-bounded transporters, called monocarboxylate transporters (MCTs) (16,24).…”