Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by mutations in the G6PC gene, encoding the catalytic subunit of
glucose-6-phosphatase. Early symptoms include severe fasting intolerance,
failure to thrive and
hepatomegaly, biochemically associated with nonketotic
hypoglycemia, fasting hyperlactidemia,
hyperuricemia and
hyperlipidemia. Dietary management is the cornerstone of treatment aiming at maintaining euglycemia, prevention of secondary metabolic perturbations and long-term complications, including liver (
hepatocellular adenomas and
carcinomas), kidney and
bone disease (hypovitaminosis D and
osteoporosis). As impaired
vitamin A homeostasis also associates with similar symptoms and is coordinated by the liver, we here analysed whether
vitamin A metabolism is affected in GSD Ia patients and liver-specific G6pc-/- knock-out mice. Serum levels of
retinol and
retinol binding protein 4 (RBP4) were significantly increased in both GSD Ia patients and L-G6pc-/- mice. In contrast, hepatic
retinol levels were significantly reduced in L-G6pc-/- mice, while hepatic
retinyl palmitate (
vitamin A storage form) and RBP4 levels were not altered. Transcript and
protein analyses indicate an enhanced production of
retinol and reduced conversion the retinoic
acids (unchanged LRAT, Pnpla2/ATGL and Pnpla3 up,
Cyp26a1 down) in L-G6pc-/- mice. Aberrant expression of genes involved in
vitamin A metabolism was associated with reduced basal
messenger RNA levels of markers of
inflammation (Cd68, Tnfα, Nos2, Il-6) and
fibrosis (Col1a1, Acta2, Tgfβ, Timp1) in livers of L-G6pc-/- mice. In conclusion, GSD Ia is associated with elevated serum
retinol and RBP4 levels, which may contribute to disease symptoms, including
osteoporosis and hepatic steatosis.