title: Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency.
abstract: OBJECTIVE
  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.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Farah
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Landau
authors.affiliation: Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: 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.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Brooks
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Suet Yin Sarah
authors.initials: SYS
authors.lastname: Fung
authors.affiliation: Faculty of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Faculty of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Boon-Huat
authors.initials: BH
authors.lastname: Bay
authors.affiliation: 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.
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
authors.affiliation: 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.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism*; D004285:Dogs; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000473:pathology*; D051379:Mice; D009929:Organ Size; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D014280:Triglycerides; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D005952:Glucose-6-Phosphatase; D020123:Sirolimus
keywords: Autophagy; GSDIa; Glucose-6-phosphatase; Glucose-6-phosphate; Glycogen; Hepatic steatosis; Lipophagy; Rapamycin; ULK1; von Gierke’s disease