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

Abstract

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.

• Authors: Benjamin L Farah, Dustin J Landau, Rohit A Sinha, Elizabeth D Brooks, Yajun Wu, Suet Yin Sarah Fung, Tomohiro Tanaka, Masahiro Hirayama, Boon-Huat Bay, Dwight D Koeberl, Paul M Yen
• Journal: Journal of hepatology (J Hepatol) Vol. 64 Issue 2 Pg. 370-379 (Feb 2016) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 26462884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Immunosuppressive Agents
• Triglycerides
• Autophagy-Related Protein-1 Homolog
• TOR Serine-Threonine Kinases
• Ulk1 protein, mouse
• Glucose-6-Phosphatase
• Sirolimus

Topics

• Animals
• Autophagy (drug effects, physiology)
• Autophagy-Related Protein-1 Homolog (metabolism)
• Dogs
• Glucose-6-Phosphatase (metabolism)
• Glycogen Storage Disease Type I (metabolism)
• Hepatocytes (metabolism)
• Immunosuppressive Agents (pharmacology)
• Lipid Metabolism (drug effects)
• Liver (pathology)
• Mice
• Organ Size
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Triglycerides (metabolism)