Cho Jun-Ho, Kim Goo-Young, Pan Chi-Jiunn, Anduaga Javier, Choi Eui-Ju, Mansfield Brian C, Chou Janice Y
Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Laboratory of Cell Death and Human Diseases, Department of Life Sciences, Korea University, Seoul, South Korea.
PLoS Genet. 2017 May 30;13(5):e1006819. doi: 10.1371/journal.pgen.1006819. eCollection 2017 May.
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.
糖原贮积病Ia型（GSD-Ia）中葡萄糖-6-磷酸酶-α（G6Pase-α）的缺乏会导致葡萄糖稳态受损和代谢表现，包括因糖原和中性脂肪积累增加而引起的肝肿大。最近的一份报告显示，G6Pase-α缺乏会导致自噬受损，自噬是细胞代谢的一个重要循环过程。然而，自噬缺陷的分子机制尚不清楚。在这里，我们表明，在小鼠中，肝脏特异性敲除G6Pase-α（L-G6pc-/-）会导致沉默调节蛋白1（SIRT1）信号下调，该信号通过自噬相关（ATG）蛋白的去乙酰化和转录因子叉头框O（FoxO）家族激活自噬，而FoxO家族可激活自噬基因。一致的是，G6Pase-α缺陷肝脏中的自噬缺陷表现为自噬成分表达减弱、ATG5和ATG7乙酰化增加、ATG5和ATG12结合减少以及自噬通量降低。我们进一步表明，肝脏G6Pase-α缺乏会导致碳水化合物反应元件结合蛋白（一种生脂转录因子）激活、过氧化物酶体增殖物激活受体-γ（PPAR-γ，一种脂质调节因子）表达增加以及脂肪酸β-氧化的主要调节因子PPAR-α表达受抑制，所有这些都导致肝脂肪变性和SIRT1表达下调。腺病毒载体介导的肝脏SIRT1表达增加可纠正自噬缺陷，但不能纠正与G6Pase-α缺乏相关的代谢异常。重要的是，重组腺相关病毒（rAAV）载体介导的肝脏G6Pase-α表达恢复可纠正代谢异常、恢复SIRT1-FoxO信号并使缺陷的自噬正常化。综上所述，这些数据表明，肝脏G6Pase-α缺乏介导的SIRT1信号下调是GSD-Ia中肝脏自噬缺陷的基础。
