MCT1 and MCT4 Expression and Lactate Flux Activity Increase During White and Brown Adipogenesis and Impact Adipocyte Metabolism

Abstract

Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in adipocytes is poorly understood. Here, we tested the hypothesis that adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for adipocyte metabolism. The mRNA and protein levels of the lactate-H+ transporter MCT1 and the Na+,HCO3 − cotransporter NBCe1 were upregulated in mouse interscapular brown and inguinal white adipose tissue upon cold induction of thermogenesis and browning. MCT1, MCT4, and NBCe1 were furthermore strongly upregulated at the mRNA and protein level upon differentiation of cultured pre-adipocytes. Adipocyte differentiation was accompanied by increased plasma membrane lactate flux capacity, which was reduced by MCT inhibition and by MCT1 knockdown. Finally, in differentiated brown adipocytes, glycolysis (assessed as ECAR), and after noradrenergic stimulation also oxidative metabolism (OCR), was decreased by MCT inhibition. We suggest that upregulation of MCT1- and MCT4-mediated lactate flux capacity and NBCe1-mediated HCO3 −/pH homeostasis are important for the physiological function of mature adipocytes.

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

“…33,34 While an increase in pH i is sufficient to induce dysplasia at least under some conditions, 35 it is also well accepted that at least NHE1 plays additional roles, including scaffolding of signaling components. While the relative roles of the transporters in pH i homeostasis may differ in vitro and in vivo, we favor the interpretation that MCT4 KD in the MDA-MB-231 cells, which lack MCT1, compromises lactate efflux so substantially that glycolysis is essentially abrogated, reducing metabolic acid production and thus allowing pH i to be maintained by other net acid extruders (NHE1 and NBCn1).…”

“…Substantiating this notion, inhibition of metabolism by MCT KD or inhibition has been demonstrated previously by us and others. 33,34 While an increase in pH i is sufficient to induce dysplasia at least under some conditions, 35 it is also well accepted that at least NHE1 plays additional roles, including scaffolding of signaling components. 36,37 An important question for future studies is, therefore, whether NHE1 and NBCn1 simply serve to regulate global tumor cell pH i or they additionally play specialized roles, e.g.…”

Statins decrease leptin expression in human white adipocytes

“…The cellular uptake of statins is known to be mediated via active transport through several proteins. Among the active transporters known to regulate the cellular influx of statins, monocarboxylate transporter-4 (MCT4) has been shown to be expressed in adipocytes and preadipocytes which may likely increase the intracellular concentrations of statins (Perez de Heredia et al 2010;Petersen et al 2017).…”

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

“…Therefore, we hypothesized that reversing an acidified microenvironment might be an effective method to rescue the cytotoxicity of NK cells. Monocarboxylic acid transporter 4 (SLC16A3/MCT4) is one of the membrane protein stubs in cells that is structurally able to output lactic and pyruvic acids and affect the acidity of the tumor microenvironments . High expression of MCT4 has been reported to be a biomarker in various types of tumors, which makes it an appealing therapeutic target in cancers.…”

“…Monocarboxylic acid transporter 4 (SLC16A3/MCT4) is one of the membrane protein stubs in cells that is structurally able to output lactic and pyruvic acids and affect the acidity of the tumor microenvironments. [15][16][17] High expression of MCT4 has been reported to be a biomarker in various types of tumors, [18][19][20][21][22][23][24] which makes it an appealing therapeutic target in cancers. The blockade of MCT4 expression has been shown to represent a novel treatment target in glioblastoma, large B-cell lymphoma, and multiple myeloma.…”