Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia

Hum Mol Genet. 2020 Jan 15;29(2):286-294. doi: 10.1093/hmg/ddz290.


Glycogen storage disease type Ia (GSD Ia) is caused by autosomal mutations in glucose-6-phosphatase α catalytic subunit (G6PC) and can present with severe hypoglycemia, lactic acidosis and hypertriglyceridemia. In both children and adults with GSD Ia, there is over-accumulation of hepatic glycogen and triglycerides that can lead to steatohepatitis and a risk for hepatocellular adenoma or carcinoma. Here, we examined the effects of the commonly used peroxisomal proliferated activated receptor α agonist, fenofibrate, on liver and kidney autophagy and lipid metabolism in 5-day-old G6pc -/- mice serving as a model of neonatal GSD Ia. Five-day administration of fenofibrate decreased the elevated hepatic and renal triglyceride and hepatic glycogen levels found in control G6pc -/- mice. Fenofibrate also induced autophagy and promoted β-oxidation of fatty acids and stimulated gene expression of acyl-CoA dehydrogenases in the liver. These findings show that fenofibrate can rapidly decrease hepatic glycogen and triglyceride levels and renal triglyceride levels in neonatal G6pc -/- mice. Moreover, since fenofibrate is an FDA-approved drug that has an excellent safety profile, our findings suggest that fenofibrate could be a potential pharmacological therapy for GSD Ia in neonatal and pediatric patients as well as for adults. These findings may also apply to non-alcoholic fatty liver disease, which shares similar pathological and metabolic changes with GSD Ia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenases / metabolism
  • Animals
  • Animals, Newborn
  • Autophagosomes / drug effects
  • Autophagosomes / pathology
  • Autophagosomes / ultrastructure
  • Autophagy / drug effects
  • Fatty Acids / metabolism
  • Fenofibrate / administration & dosage
  • Fenofibrate / pharmacology*
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / metabolism*
  • Glycogen / metabolism*
  • Glycogen Storage Disease Type I / enzymology
  • Glycogen Storage Disease Type I / genetics
  • Glycogen Storage Disease Type I / metabolism*
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Lipid Metabolism / drug effects*
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Liver / ultrastructure
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Triglycerides / metabolism


  • Fatty Acids
  • PPAR alpha
  • Triglycerides
  • Glycogen
  • Acyl-CoA Dehydrogenases
  • Glucose-6-Phosphatase
  • Fenofibrate