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Title: Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency
Authors: Farah B.L.
Landau D.J.
Sinha R.A. 
Brooks E.D.
Wu Y. 
Fung S.Y.S. 
Tanaka T.
Hirayama M.
Bay B.-H. 
Koeberl D.D.
Yen P.M. 
Keywords: Lipophagy
von Gierke�s disease
Hepatic steatosis
Issue Date: 2016
Publisher: Elsevier
Citation: Farah B.L., Landau D.J., Sinha R.A., Brooks E.D., Wu Y., Fung S.Y.S., Tanaka T., Hirayama M., Bay B.-H., Koeberl D.D., Yen P.M. (2016). Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. Journal of Hepatology 64 (2) : 370-379. ScholarBank@NUS Repository.
Abstract: Background & Aims Glucose-6-phosphatase (G6Pase ?, 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 ?-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.
Source Title: Journal of Hepatology
ISSN: 1688278
DOI: 10.1016/j.jhep.2015.10.008
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