Down-regulation of the hexose transport system: metabolic basis studied with a fibroblast mutant lacking phosphoglucose isomerase.

Abstract

Down-regulation ("curb") of hexose transport in Chinese hamster lung fibroblasts has been studied in a metabolic mutant highly defective in phosphoglucose isomerase (PGI; glucosephosphate isomerase; D-glucose-6-phosphate ketol-isomerase, EC 5.3.1.9). In the parental strain (PGI+) glucose as well as glucosamine and mannose were able to elicit a curb of the hexose transport system. In the PGI mutant, only glucose was able to mediate a transport curb. The inability of glucosamine and mannose to promote a transport curb in the PGV strain must be ascribed to the fact that the 6-esters of these aldohexoses are converted by their own specific deaminase and isomerase to fructose 6-phosphate, which initiates the pyruvate-tricarboxylate energyyielding pathway but cannot be converted to glucose 6-phosphate in the mutant. The latter ester can be metabolized, but its metabolism in the mutant is confined to the pentose shunt. It is shown that inhibitors such as 2,4-dinitrophenol and malonate exert only slight inhibition of the pentose shunt yet release the glucose-mediated curb elicited by glucose and glucosamine in the parental PGI+ strain and also the glucose transport curb persisting in the PGI mutant.It has recently been observed in cultured hamster fibroblasts that glucose-mediated down-regulation of the hexose transport system (abbreviated "transport curb") was released by addition of 2,4-dinitrophenol (DNP), oligomycin, and malonate (1, 2). Because these inhibitors also interfere with oxidative phosphorylation and the tricarboxylate cycle, one is led to believe that oxidative energy metabolism may be crucial for the preservation of the transport curb (2).The role of lactic acid generation for the establishment ofthe transport curb was considered dubious, especially after it was disclosed that the amino sugar D-glucosamine exerts a marked transport curb of the hexose transport system, yet only traces of lactic acid are generated (1, 2).Fructose, a furanoid ketohexose, is recognized neither by the hexose transporter from erythrocytes (3) nor by that of hamster fibroblasts (see table 1 of ref. 2). Yet the catabolism offructose, via fructose 6-phosphate (Fru-6-P), is presumably much like that of D-glucosamine.The glucose-mediated transport curb and its release by glucose starvation has recently been studied on a tumor line, 023, from Chinese hamster lung fibroblasts (4). In contrast to other fibroblast lines, in which the presence of cycloheximide at the onset of glucose starvation interferes with the release of the transport curb (5, 6), no interference was observed in 023 (4).In 1980, Pouyssegur et al. (7) isolated and characterized a metabolic mutant called DS-7. It was shown (7) to be highly defective in the enzyme phosphoglucose isomerase (PGI; glucosephosphate isomerase; D-glucose-6-phosphate ketol-isomerase, EC 5.3.1.9).This strain and the parental strain 023 are tumorigenic lines, although DS-7 is nonglycolytic (8). For the sake of clarity, we shall call the DS-7 strain with the defect in phosphoglucose is...

MondoA Senses Non-glucose Sugars

“…Furthermore, consistent with previous reports (34), DNP reversed the hexose transport curb (Fig. 6B).…”

“…The hexose transport curb is not a passive response of cells to accumulated Glc-6-P, but rather requires initial feeding with a hexose, an intact oxidative phosphorylation pathway, and protein synthesis (13,14,27,31,34). Our data suggest that the MondoA-TXNIP negative feedback circuit is a required component of the hexose transport curb.…”

Effect of high glucose on formation of extracellular matrix components by cultured rat heart endothelial cells

“…eration stimulated by excess glucose metabolism occurs soon after treatment begins. This observed reduction in glucose uptake with time is consistent 11. with previous reports of hexose transport down-regulation in cultured ceils [30] and mRNA levels for GLUT1 have been found to be consistent with the transport changes observed, namely being increased after glucose starvation and conversely decreased 12. after treatment with more than 15 mmol/1 glucose [31][32][33]. Although glucose metabolism is required 13. for this regulation of hexose transport, the exact signals for altered transcription are still unclear.…”

“…Although glucose metabolism is required 13. for this regulation of hexose transport, the exact signals for altered transcription are still unclear. Just as collagens IV and VI are differentially regulated by 435 glucose and metabolites such as pyruvate [3], transport down-regulation is promoted by glucosamine and mannose but not fructose [30], which would be expected to enter the metabolic pathway at the same point. Concomitant investigation of regulation of both extracellular matrix formation and hexose transport may therefore provide valuable clues to the early events occurring after exposure of cells to elevated glucose concentrations.…”

Glucose entry into rat mesangial cells is mediated by both Na+-coupled and facilitative transporters

“…The decrease which we noted in both the Na+-dependent and facilitated transport of mesangial cells in response to their exposure to high glucose is similar to that observed in the LLC-PK 1 kidney epithelial cell line [21]; glucose-induced down-regulation of hexose transporters has been reported to occur in a variety of cells [25,36,37] as well as in renal brush border membrane vesicles from diabetic rats [38]. However, we have noticed that in cultured mesangial cells, despite down-regulation of the transporters in the presence of elevated glucose, the net glucose consumption remains substantially increased and is accompanied by a highly significant M. Wakisaka, et al: Glucose transporters of rat mesangial cells enhancement in type IV and VI collagen production [7].…”