Minimal hepatic glucose-6-phosphatase-? activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia.
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ABSTRACT: Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-? (G6Pase-? or G6PC) activity. In a previous 70-90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-? activity in G6pc (-/-) mice corrects hepatic G6Pase-? deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-? activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc (-/-) mice expressing 0.2% of wild-type hepatic G6Pase-? activity suffered from frequent hypoglycemic seizures at age 63-65 weeks but mice expressing 0.5-1.3% of wild-type hepatic G6Pase-? activity (AAV-LL mice) sustain 4-6 h of fast and grow normally to age 75-90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-?/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-? gene-based therapy for GSD-Ia.
SUBMITTER: Lee YM
PROVIDER: S-EPMC4750588 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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