{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:15:44Z","timestamp":1790298944683,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"2","funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD000912-38"],"award-info":[{"award-number":["HD000912-38"]}],"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":[[2023,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Type Ib glycogen storage disease (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that translocates G6P from the cytoplasm into the endoplasmic reticulum lumen, where the intraluminal G6P is hydrolyzed to glucose by glucose-6-phosphatase-\u03b1 (G6Pase-\u03b1). Clinically, GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and a long-term risk of hepatocellular adenoma\/carcinoma (HCA\/HCC). Studies have shown that autophagy deficiency contributes to hepatocarcinogenesis. In this study, we show that G6PT deficiency leads to impaired hepatic autophagy evident from attenuated expression of many components of the autophagy network, decreased autophagosome formation and reduced autophagy flux. The G6PT-deficient liver displayed impaired sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) signaling, along with reduced expression of SIRT1, forkhead boxO3a (FoxO3a), liver kinase B-1 (LKB1) and the active p-AMPK. Importantly, we show that overexpression of either SIRT1 or LKB1 in G6PT-deficient liver restored autophagy and SIRT1\/FoxO3a and LKB1\/AMPK signaling. The hepatosteatosis in G6PT-deficient liver decreased SIRT1 expression. LKB1 overexpression reduced hepatic triglyceride levels, providing a potential link between LKB1\/AMPK signaling upregulation and the increase in SIRT1 expression. In conclusion, downregulation of SIRT1\/FoxO3a and LKB1\/AMPK signaling underlies impaired hepatic autophagy which may contribute to HCA\/HCC development in GSD-Ib. Understanding this mechanism may guide future therapies.<\/jats:p>","DOI":"10.1093\/hmg\/ddac197","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T21:11:03Z","timestamp":1660338663000},"page":"262-275","source":"Crossref","is-referenced-by-count":14,"title":["Molecular mechanism underlying impaired hepatic autophagy in glycogen storage disease type Ib"],"prefix":"10.1093","volume":"32","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, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zhang","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol","family":"Lee","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Arnaoutova","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung Dar","family":"Chen","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Resaz","sequence":"additional","affiliation":[{"name":"Istituto Giannina Gaslini , Largo Gaslini 5, 16147, Genoa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Eva","sequence":"additional","affiliation":[{"name":"Istituto Giannina Gaslini , Largo Gaslini 5, 16147, Genoa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C","family":"Mansfield","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice Y","family":"Chou","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20802 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"2023042922553437100_ref1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nrendo.2010.189","article-title":"Glycogen storage disease type I and G6Pase-\u03b2 deficiency: etiology and therapy","volume":"6","author":"Chou","year":"2010","journal-title":"Nat. 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