Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency.

Journal Article (Journal Article)

BACKGROUND & AIMS: Glucose-6-phosphatase (G6Pase α, G6PC) deficiency, also known as von Gierke's disease or GSDIa, is the most common glycogen storage disorder. It is characterized by a decreased ability of the liver to convert glucose-6-phosphate (G6P) to glucose leading to glycogen and lipid over-accumulation progressing to liver failure and/or hepatomas and carcinomas. Autophagy of intracellular lipid stores (lipophagy) has been shown to stimulate fatty acid β-oxidation in hepatic cells. Thus, we examined autophagy and its effects on reducing hepatic lipid over-accumulation in several cell culture and animal models of GSDIa. METHODS: Autophagy in G6PC-deficient hepatic cell lines, mice, and dogs was measured by Western blotting for key autophagy markers. Pro-autophagic Unc51-like kinase 1 (ULK1/ATG1) was overexpressed in G6PC-deficient hepatic cells, and lipid clearance and oxidative phosphorylation measured. G6PC(-/-) mice and GSDIa dogs were treated with rapamycin and assessed for liver function. RESULTS: Autophagy was impaired in the cell culture, mouse, and canine models of GSDIa. Stimulation of the anti-autophagic mTOR, and inhibition of the pro-autophagic AMPK pathways occurred both in vitro and in vivo. Induction of autophagy by ULK1/ATG1 overexpression decreased lipid accumulation and increased oxidative phosphorylation in G6PC-deficient hepatic cells. Rapamycin treatment induced autophagy and decreased hepatic triglyceride and glycogen content in G6PC(-/-) mice, as well as reduced liver size and improved circulating markers of liver damage in GSDIa dogs. CONCLUSIONS: Autophagy is impaired in GSDIa. Pharmacological induction of autophagy corrects hepatic lipid over-accumulation and may represent a new therapeutic strategy for GSDIa.

Full Text

Duke Authors

Cited Authors

  • Farah, BL; Landau, DJ; Sinha, RA; Brooks, ED; Wu, Y; Fung, SYS; Tanaka, T; Hirayama, M; Bay, B-H; Koeberl, DD; Yen, PM

Published Date

  • February 2016

Published In

Volume / Issue

  • 64 / 2

Start / End Page

  • 370 - 379

PubMed ID

  • 26462884

Electronic International Standard Serial Number (EISSN)

  • 1600-0641

Digital Object Identifier (DOI)

  • 10.1016/j.jhep.2015.10.008


  • eng

Conference Location

  • Netherlands