High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes.

Abstract

The regenerating liver after partial hepatectomy is one of the few physiologic models of cellular proliferation in the adult animal. During hepatic regeneration, the animal is able to maintain metabolic homeostasis despite the acute loss of two thirds of hepatic tissue. In examining the molecular mechanisms regulating hepatic regeneration, we isolated novel immediate-early genes that are rapidly induced as the remnant liver undergoes the transition from its normal quiescent state into the G1 phase of the cell cycle. One of the most rapidly and highly induced genes which we initially termed RL-1, encodes rat glucose-6-phosphatase (rG6Pase). G6Pase mRNA peaks at 30 min and 36-48 h after hepatectomy correlating with the first and second rounds of cell division. This finding is compatible with studies that showed that G6Pase enzyme activity increases during liver regeneration. However, the increase in G6Pase mRNA is much more dramatic, indicating that it is a more sensitive indicator of this regulation. G6Pase gene expression peaks in the perinatal time period in the liver and remains elevated during the first month of life. The expression of the G6Pase gene is also dramatically elevated in BB diabetic rats, again higher than the enzyme elevation, and its relative induction after partial hepatectomy is blunted in these animals. Insulin treatment of partially hepatectomized diabetic animals downregulates the expression of G6Pase mRNA. Using specific antibodies against G6Pase, we detect a 36-kD G6Pase protein, and its level is elevated in regenerating and diabetic livers. The pattern of G6Pase mRNA expression appears to reflect similar changes in insulin and glucagon levels which accompany diabetes and hepatic proliferation. The elevation of G6Pase expression in these conditions is indicative of its importance as a regulator of glucose homeostasis in normal and abnormal physiologic states. (J. Clin. Invest. 1995. 95:832-841.)

Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer

“…On the other hand, increased hepatic G6Pase-a activity has been found in human diabetes 33 and in experimental rodent diabetic models. 34,35 Thus, constitutively high-level hepatic G6Pase-a expression may lead to the development of diabetes, and warrants further investigation.…”

Cloning and sequencing of the 5′ region of the human glucose‐6‐phosphatase gene: transcriptional regulation by cAMP, insulin and glucocorticoids in H4IIE hepatoma cells

“…However, from animal studies it is clear that hepatic glucose-6-phosphatase is regulated. Hepatic glucose-6-phosphatase enzyme activity [1,8], protein levels [8], and mRNA levels [9] all increase greatly in animal models of diabetes mellitus. Administration of glucocorticoids, insulin, thyroid hormone or glucagon to animals has been shown to alter glucose-6-phosphatase activity in microsomes [1,[10][11][12][13].…”

“…Administration of glucocorticoids, insulin, thyroid hormone or glucagon to animals has been shown to alter glucose-6-phosphatase activity in microsomes [1,[10][11][12][13]. In addition, liver glucose-6-phosphatase enzyme activity, protein and mRNA levels are developmentally regulated in mammals [9,14,15]. It therefore seems likely that a number of cis-acting elements will be present in the promoter regulatory region of the glucose-6-phosphatase gene to confer these multiple modes of regulation but to date the 5' region of the gene has not been characterised and very little is known about the mechanisms of hormonal regulation of glucose-6-phosphatase gene expression [16].…”

Identification of protein components of the microsomal glucose 6-phosphate transporter by photoaffinity labelling

“…Triton X-1002, CHAPS, Serva Blue R-250 and Western-light chemiluminescence detection kit and all other materials for electrophoresis were from Serva (Heidelberg, Germany). Antibodies raised against glucose-6-phosphatase were kindly provided by Dr. Rebecca Taub (University of Pennsylvania, Philadelphia, PA, U.S.A.) [25]. Polyclonal anti-(glucose-6-phosphate translocase) antibodies were generated in rabbit by Eurogentec (Lie!…”