Brain Contains a Functional Glucose-6-Phosphatase Complex Capable of Endogenous Glucose Production

Abhijit Ghosh,Yuk Yin Cheung,Brian C Mansfield,Janice Yang Chou

doi:10.1074/jbc.m410894200

Abstract

Glucose is absolutely essential for the survival and function of the brain. In our current understanding, there is no endogenous glucose production in the brain, and it is totally dependent upon blood glucose. This glucose is generated between meals by the hydrolysis of glucose-6-phosphate (Glc-6-P) in the liver and the kidney. Recently, we reported a ubiquitously expressed Glc-6-P hydrolase, glucose-6-phosphatase-beta (Glc-6-Pase-beta), that can couple with the Glc-6-P transporter to hydrolyze Glc-6-P to glucose in the terminal stages of glycogenolysis and gluconeogenesis. Here we show that astrocytes, the main reservoir of brain glycogen, express both the Glc-6-Pase-beta and Glc-6-P transporter activities and that these activities can couple to form an active Glc-6-Pase complex, suggesting that astrocytes may provide an endogenous source of brain glucose.

Highlights

Glc-6-Pase-␣ [15], Glc-6-Pase-␤ [16], and Glc-6-PT [17] are co-localized in the membrane of the endoplasmic reticulum (ER), embedded by multiple transmembrane domains
Blood glucose homeostasis between meals is maintained by balancing the blood glucose uptake by tissues with the release of Glc-6-P-derived glucose to the blood by the liver and kidney
Specific Glc-6-Pase activity has not been detected outside of the liver, kidney, and intestine. This has led to the current view that interprandial glucose homeostasis depends solely upon these organs

Summary

The abbreviations used are

Glc-6-Pase, glucose-6-phosphatase; Glc6-P, glucose-6-phosphate; Glc-PT, glucose-6-phosphate transporter; hGlc-6-Pase, human Glc-6-Pase; mGlc-6-Pase, mouse Glc-6-Pase; Ad, adenovirus; ER, endoplasmic reticulum; GFAP, glial fibrillary acidic protein; pfu, plaque-forming units. Glc-6Pase-␤ is a 346-amino acid phosphohydrolase [13, 14] expressed ubiquitously [12] Both exhibit similar active site structures, form similar covalently bound phosphoryl enzyme intermediates during catalysis [16, 20], and exhibit similar kinetic properties [14]. The discovery of Glc-6-Pase-␤ implies that non-hepatic tissues may be capable of endogenous glucose production through the activity of a Glc-6-Pase-␤1⁄7Glc-6-PT complex. This is of particular interest, because the liver and kidney are not the sole sites of glycogen storage in the body. The role of astrocyte glycogen in glucose production is controversial because the presence of a functional Glc-6-Pase complex has never been demonstrated in the brain. We show that brain astrocytes possess an active Glc-6-Pase-␤1⁄7Glc-6-PT complex that can hydrolyze Glc-6-P to glucose, suggesting that astrocyte glycogen can be converted to glucose and may be a source of alternative energy in the neurons

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION