Benjamin L Farah1, Dustin J Landau2, Rohit A Sinha1, Elizabeth D Brooks3, Yajun Wu4, Suet Yin Sarah Fung5, Tomohiro Tanaka6, Masahiro Hirayama6, Boon-Huat Bay4, Dwight D Koeberl7, Paul M Yen8. 1. Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore. 2. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. 3. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA. 4. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 5. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore. 6. Faculty of Medicine, Tohoku University, Sendai, Japan. 7. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA. Electronic address: dwight.koeberl@duke.edu. 8. Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore; Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. Electronic address: paul.yen@duke-nus.edu.sg.
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.
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.
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Authors: Lauren R Waskowicz; Jin Zhou; Dustin J Landau; Elizabeth D Brooks; Andrea Lim; Zollie A Yavarow; Tsubasa Kudo; Haoyue Zhang; Yajun Wu; Stuart Grant; Sarah P Young; Bay Boon Huat; Paul M Yen; Dwight D Koeberl Journal: Hum Mol Genet Date: 2019-01-01 Impact factor: 6.150
Authors: Elizabeth D Brooks; Dustin J Landau; Jeffrey I Everitt; Talmage T Brown; Kylie M Grady; Lauren Waskowicz; Cameron R Bass; John D'Angelo; Yohannes G Asfaw; Kyha Williams; Priya S Kishnani; Dwight D Koeberl Journal: J Inherit Metab Dis Date: 2018-07-24 Impact factor: 4.982