Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia.

Journal Article (Journal Article)

Glucose-6-phosphatase α (G6Pase) deficiency, also known as von Gierke's Disease or Glycogen storage disease type Ia (GSD Ia), is characterized by decreased ability of the liver to convert glucose-6-phosphate to glucose leading to glycogen accumulation and hepatosteatosis. Long-term complications of GSD Ia include hepatic adenomas and carcinomas, in association with the suppression of autophagy in the liver. The G6pc-/- mouse and canine models for GSD Ia were treated with the pan-peroxisomal proliferator-activated receptor agonist, bezafibrate, to determine the drug's effect on liver metabolism and function. Hepatic glycogen and triglyceride concentrations were measured and western blotting was performed to investigate pathways affected by the treatment. Bezafibrate decreased liver triglyceride and glycogen concentrations and partially reversed the autophagy defect previously demonstrated in GSD Ia models. Changes in medium-chain acyl-CoA dehydrogenase expression and acylcarnintine flux suggested that fatty acid oxidation was increased and fatty acid synthase expression associated with lipogenesis was decreased in G6pc-/- mice treated with bezafibrate. In summary, bezafibrate induced autophagy in the liver while increasing fatty acid oxidation and decreasing lipogenesis in G6pc-/- mice. It represents a potential therapy for glycogen overload and hepatosteatosis associated with GSD Ia, with beneficial effects that have implications for non-alcoholic fatty liver disease.

Full Text

Duke Authors

Cited Authors

  • Waskowicz, LR; Zhou, J; Landau, DJ; Brooks, ED; Lim, A; Yavarow, ZA; Kudo, T; Zhang, H; Wu, Y; Grant, S; Young, SP; Huat, BB; Yen, PM; Koeberl, DD

Published Date

  • January 1, 2019

Published In

Volume / Issue

  • 28 / 1

Start / End Page

  • 143 - 154

PubMed ID

  • 30256948

Pubmed Central ID

  • PMC6298237

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddy343


  • eng

Conference Location

  • England