{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:15:36Z","timestamp":1788156936961,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Fatty liver is considered the pathological basis for the development of glycogen storage disease type Ia (GSDIa); however, due to the lack of suitable animal models, the mechanism underlying fatty liver development in GSDIa is largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study employed surrogate breastfeeding to enable the survival of glucose-6-phosphatase catalytic (\n                      <jats:italic>G6PC<\/jats:italic>\n                      ) knockout (KO) mice into adulthood, and then analyzed fatty liver phenotypes in 3-month-old KO (KO-3), 6-month-old KO (KO-6), and 9-month-old KO (KO-9) mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      KO-6 and KO-9 mice exhibited typical fatty liver phenotypes, and upregulation of glucose-6-phosphate (G6P). Moreover, both Western blot and qRT-PCR analysis showed significant upregulation of ChREBP, SREBP1 and fatty acid synthesis enzymes. RNA-seq heat maps revealed that KO-6 and KO-9 mice exhibited similar expression patterns, distinct from those observed in the wild-type (WT) and KO-3 groups. GO and KEGG analysis further revealed changes in lipid metabolism pathways in KO-6 and KO-9 mice, as well as PI3K-Akt, AMPK, and MAPK signaling. Western blot analysis showed that the Akt and mTOR pathways were activated, while the AMPK pathway was downregulated, indicating impaired autophagy. Finally, bezafibrate, a proliferator-activated receptor \u03b1 (PPAR-\u03b1) agonist, enhanced autophagic activity and attenuated inflammatory responses, fat deposition, and glycogen storage in\n                      <jats:italic>G6PC<\/jats:italic>\n                      KO mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study successfully generated a fatty liver model using\n                      <jats:italic>G6PC<\/jats:italic>\n                      KO adult mice and demonstrated that pharmacological activation of PPAR-\u03b1 may have therapeutic potential in adult\n                      <jats:italic>G6PC<\/jats:italic>\n                      KO mice.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1898810","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:39:34Z","timestamp":1788154774000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Generation of a glycogen storage disease mouse model with fatty liver and its treatment by PPAR-\u03b1 agonist bezafibrate"],"prefix":"10.3389","volume":"17","author":[{"given":"Yixia","family":"Xie","sequence":"first","affiliation":[{"name":"School of Life and Environmental Sciences, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoquan","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Shaoxing University","place":["Shaoxing, Zhejiang, China"]},{"name":"Hangzhou Hongwang Medical Laboratory Co. Ltd","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huarong","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Life and Environmental Science, Hangzhou Normal University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifang","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Shaoxing University","place":["Shaoxing, Zhejiang, China"]},{"name":"Hangzhou Hongwang Medical Laboratory Co. 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