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Glucose production is concentrated in periportal hepatocytes and depends on G6PC1; loss of this enzyme causes glycogen storage disease type Ia (GSD1a). We tested whether G6PC1 loss in specific zones, including its primary periportal location, is sufficient to cause disease. Unexpectedly, loss of\n                  <jats:italic>G6pc1<\/jats:italic>\n                  in any single zone caused local glycogen accumulation but did not produce the systemic metabolic abnormalities or liver tumors seen after whole-liver deletion. Instead, disease developed only after near-complete loss of\n                  <jats:italic>G6pc1<\/jats:italic>\n                  across the entire liver. These findings show that organ-wide compensation preserves metabolic homeostasis and suppresses tumorigenesis despite localized disruption.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Teaser<\/jats:title>\n                  <jats:p>\n                    Spatial\n                    <jats:italic>G6pc1<\/jats:italic>\n                    loss causes local glycogen storage without systemic metabolic disease.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.26.740786","type":"posted-content","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T16:55:18Z","timestamp":1785257718000},"source":"Crossref","is-referenced-by-count":0,"title":["The liver compensates for zonal loss of glucose 6-phosphatase to prevent glycogen storage disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3950-9520","authenticated-orcid":false,"given":"Roger","family":"Liang","sequence":"first","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Cai","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phong T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherwin","family":"Kelekar","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie B.","family":"Cervantes","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Tippetts","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Chen","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Ribas","sequence":"additional","affiliation":[{"name":"Center for Spatial Biomolecule Research, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Ryan","sequence":"additional","affiliation":[{"name":"Center for Spatial Biomolecule Research, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","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 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-1850","authenticated-orcid":false,"given":"Ramon","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Spatial Biomolecule Research, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA"},{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA"},{"name":"Evelyn F. and William L. 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