A molecular link between the common phenotypes of type 1 glycogen storage disease and HNF1alpha-null mice.

Abstract The clinical manifestations of type 1 glycogen storage disease (GSD-1) in patients deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are shared by Hnf1α−/− mice deficient of a transcriptional activator, hepatocyte nuclear factor 1α (HNF1α). However, the molecular mechanism is unknown. The G6Pase system, essential for the maintenance of glucose homeostasis, is comprised of glucose 6-phosphate transporter (G6PT) and G6Pase. G6PT translocates G6P from the cytoplasm to the lumen of the endoplasmic reticulum where it is metabolized by G6Pase to glucose and phosphate. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively.Hnf1α−/− mice also develop noninsulin-dependent diabetes mellitus caused by defective insulin secretion. In this study, we sought to determine whether there is a molecular link between HNF1α deficiency and function of the G6Pase system. Transactivation studies revealed that HNF1α is required for transcription of the G6PT gene. Hepatic G6PT mRNA levels and microsomal G6P transport activity are also markedly reduced in Hnf1α−/− mice as compared withHnf1α+/+ andHnf1α+/− littermates. On the other hand, hepatic G6Pase mRNA expression and activity are up-regulated inHnf1α−/− mice, consistent with observations that G6Pase expression is increased in diabetic animals. Taken together, the results strongly suggest that metabolic abnormalities in HNF1α-null mice are caused in part by G6PT deficiency and by perturbations of the G6Pase system.