A molecular link between the common phenotypes of type 1 glycogen storage disease and HNF1 alpha-null mice

The clinical manifestations of type 1 glycogen storage disease (GSD-1) in p atients deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are shar ed by Hnf1 alpha (-/-) mice deficient of a transcriptional activator, hepat ocyte nuclear factor 1 alpha (HNF1 alpha). However, the molecular mechanism is unknown. The G6Pase system, essential for the maintenance of glucose ho meostasis, is comprised of glucose 6-phosphate transporter (G6PT) and G6Pas e. G6PT translocates G6P from the cytoplasm to the lumen of the endoplasmic reticulum where it is metabolized by G6Pase to glucose and phosphate, Defi ciencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Hnf1 alp ha (-/-) 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 HNF1 alpha deficiency and function of th e G6Pase system. Transactivation studies revealed that HNF1 alpha is requir ed for transcription of the G6PT gene. Hepatic G6PT mRNA levels and microso mal G6P transport activity are also markedly reduced in Hnf1 alpha (-/-) mi ce as compared with Hnf1 alpha (+/+) and Hnf1 alpha (+/-) littermates. On t he other hand, hepatic G6Pase mRNA expression and activity are up-regulated in Hnf1 alpha (-/-) mice, consistent with observations that: G6Pase expres sion is increased in diabetic animals. Taken together, the results strongly suggest that metabolic abnormalities in HNF1 alpha -null mice are caused i n part by G6PT deficiency and by perturbations of the G6Pase system.