{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:26:36Z","timestamp":1788888396915,"version":"build-2803163510"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"5","funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Glucose-6-phosphatase-\u03b1 (G6Pase-\u03b1 or G6PC) deficiency in glycogen storage disease type-Ia (GSD-Ia) leads to impaired hepatic autophagy, a recycling process important for cellular metabolism and homeostasis. Autophagy can be regulated by several energy sensing pathways, including sirtuin 1 (SIRT1), forkhead box O (FoxO), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-\u03b1 (PPAR-\u03b1), and mammalian target of rapamycin (mTOR). Using 10-day old global G6pc-deficient (G6pc\u2212\/\u2212) mice, hepatic autophagy impairment was attributed to activation of mTOR and inhibition of AMPK signaling. In other studies, using adult liver-specific G6pc-deficient mice at both pre-tumor and tumor stages, hepatic autophagy impairment was attributed to downregulation of SIRT1 signaling and mTOR was not implicated. In this study, we provide a detailed analysis of the major autophagy pathways in young G6pc\u2212\/\u2212 mice over the first 4\u00a0weeks of life. We show that impaired SIRT1, FoxO3a, AMPK, and PPAR-\u03b1 signaling are responsible for autophagy impairment but mTOR is involved minimally. Hepatic SIRT1 overexpression corrects defective autophagy, restores the expression of FoxO3a and liver kinase B1 but fails to normalize impaired PPAR-\u03b1 expression or metabolic abnormalities associated with GSD-Ia. Importantly, restoration of hepatic G6Pase-\u03b1 expression in G6pc\u2212\/\u2212 mice corrects defective autophagy, restores SIRT1\/FoxO3a\/AMPK\/PPAR-\u03b1 signaling and rectifies metabolic abnormalities. Taken together, these data show that hepatic autophagy impairment in GSD-Ia is mediated by downregulation of SIRT1\/FoxO3a\/AMPK\/PPAR-\u03b1 signaling.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa007","type":"journal-article","created":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T04:22:36Z","timestamp":1579148556000},"page":"834-844","source":"Crossref","is-referenced-by-count":21,"title":["The signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type Ia"],"prefix":"10.1093","volume":"29","author":[{"given":"Sudeep","family":"Gautam","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zhang","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Arnaoutova","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol","family":"Lee","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C","family":"Mansfield","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development"},{"name":"Foundation Fighting Blindness, Columbia, MD 21046, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice Y","family":"Chou","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"2020033008550221600_ref1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nrendo.2010.189","article-title":"Glycogen storage disease type I and G6Pase-beta deficiency: etiology and therapy","volume":"6","author":"Chou","year":"2010","journal-title":"Nat. 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