Downregulation of SIRT1 signaling underlies hepatic autophagy impairment in glycogen storage disease type Ia

A deficiency in glucose-6-phosphatase-α (g6pase-α) in glycogen storage disease type ia (gsd-ia) leads to impaired glucose homeostasis and metabolic manifestations including hepatomegaly caused by increased glycogen and neutral fat accumulation. a recent report showed that g6pase-α deficiency causes impairment in autophagy,a recycling process important for cellular metabolism. however,the molecular mechanism underlying defective autophagy is unclear. here we show that in mice,liver-specific knockout of g6pase-α (l-g6pc-/-) leads to downregulation of sirtuin 1 (sirt1) signaling that activates autophagy via deacetylation of autophagy-related (atg) proteins and forkhead box o (foxo) family of transcriptional factors which transactivate autophagy genes. consistently,defective autophagy in g6pase-α-deficient liver is characterized by attenuated expressions of autophagy components,increased acetylation of atg5 and atg7,decreased conjugation of atg5 and atg12,and reduced autophagic flux. we further show that hepatic g6pase-α deficiency results in activation of carbohydrate response element-binding protein,a lipogenic transcription factor,increased expression of peroxisome proliferator-activated receptor-γ (ppar-γ),a lipid regulator,and suppressed expression of ppar-α,a master regulator of fatty acid β-oxidation,all contributing to hepatic steatosis and downregulation of sirt1 expression. an adenovirus vector-mediated increase in hepatic sirt1 expression corrects autophagy defects but does not rectify metabolic abnormalities associated with g6pase-α deficiency. importantly,a recombinant adeno-associated virus (raav) vector-mediated restoration of hepatic g6pase-α expression corrects metabolic abnormalities,restores sirt1-foxo signaling,and normalizes defective autophagy. taken together,these data show that hepatic g6pase-α deficiency-mediated down-regulation of sirt1 signaling underlies defective hepatic autophagy in gsd-ia. © 2017 public library of science. all rights reserved.