{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/10442"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/10442","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Glucose-6-Phosphatase in Metabolic Disease and Cancer","abstract":"Inborn errors of metabolism (IEMs), which are caused by germline mutations in metabolic enzymes and nutrient transporters, provide an opportunity to observe how discrete metabolic defects cause human disease. Glycogen Storage Disease Type 1a (GSD1a), or von Gierke's disease, is an autosomal recessive IEM caused by defects in Glucose-6-Phosphatase, Catalytic Subunit (G6PC), the terminal enzyme in both glycogenolysis and gluconeogenesis. Fasting hypoglycemia, a prominent symptom of GSD1a, is understandable because of G6PC's role in hepatic glucose output. Other metabolic anomalies in GSD1a, including debilitating lactic acidosis and hyperuricemia, are assumed to be consequences of glucose-6-phosphate accumulation, although the mechanism has not been explored in detail. Late sequela of GSD1a includes the formation of liver adenomas and carcinomas without obvious signs of liver injury or cirrhosis. Here we show that the oncogenic transcription factor c-Myc potentiates metabolic rewiring and drives lactic acidosis and hyperuricemia in a mouse model of GSD1a. Using metabolic profiling and isotope labeling strategies in both in vivo and cultured cell models of GSD1a, we found enhanced use of both glycolysis and the pentose phosphate pathway, which produce precursors to lactate and urate, respectively. Transcriptomic analysis revealed that these metabolic changes were accompanied by increased transcription of genes in both pathways. In addition to stimulating these metabolic pathways, we observed that G6PC deletion stimulates hepatocyte proliferation in culture and in the liver. Overall, the transcriptomic profile of G6PC-deficient livers indicated enhanced expression of c-Myc-responsive genes, and c-Myc itself was markedly induced within two weeks of G6PC deletion. c-Myc regulates many aspects of glucose metabolism in cancer, and 75% of GSD1a patients eventually develop hepatic adenomas (HCAs) and hepatocellular carcinomas (HCCs). However, c-Myc activation occurred long before the appearance of malignancy in these mice. We tested if c-Myc potentiates the metabolic anomalies initiated by G6PC deletion. We found modest genetic silencing of c-Myc normalized genes and metabolites related to glycolysis and the pentose phosphate pathway. In both the liver and a hepatocyte cell line, suppressing c-Myc attenuated the accumulation of lactate and urate, despite persistent G6PC deficiency and glycogen accumulation. We found that G6PC deficiency induces a hyperproliferative state in a hepatocyte cell line and premalignant livers, and c-Myc silencing reduced these effects. Finally, we characterized tumors that form in GSD1a as having a strong c-Myc gene signature as well as a low mutational burden relative to sporadic liver cancers, without signs of liver injury or cirrhosis. Overall, our results demonstrate that a monogenic metabolic defect in a human IEM induces a localized oncogenic response in the liver that drives systemic metabolic dysfunction and may contribute to carcinogenesis.","abstract_html":"Inborn errors of metabolism (IEMs), which are caused by germline mutations in metabolic enzymes and nutrient transporters, provide an opportunity to observe how discrete metabolic defects cause human disease. Glycogen Storage Disease Type 1a (GSD1a), or von Gierke's disease, is an autosomal recessive IEM caused by defects in Glucose-6-Phosphatase, Catalytic Subunit (G6PC), the terminal enzyme in both glycogenolysis and gluconeogenesis. Fasting hypoglycemia, a prominent symptom of GSD1a, is understandable because of G6PC's role in hepatic glucose output. Other metabolic anomalies in GSD1a, including debilitating lactic acidosis and hyperuricemia, are assumed to be consequences of glucose-6-phosphate accumulation, although the mechanism has not been explored in detail. Late sequela of GSD1a includes the formation of liver adenomas and carcinomas without obvious signs of liver injury or cirrhosis. Here we show that the oncogenic transcription factor c-Myc potentiates metabolic rewiring and drives lactic acidosis and hyperuricemia in a mouse model of GSD1a. Using metabolic profiling and isotope labeling strategies in both in vivo and cultured cell models of GSD1a, we found enhanced use of both glycolysis and the pentose phosphate pathway, which produce precursors to lactate and urate, respectively. Transcriptomic analysis revealed that these metabolic changes were accompanied by increased transcription of genes in both pathways. In addition to stimulating these metabolic pathways, we observed that G6PC deletion stimulates hepatocyte proliferation in culture and in the liver. Overall, the transcriptomic profile of G6PC-deficient livers indicated enhanced expression of c-Myc-responsive genes, and c-Myc itself was markedly induced within two weeks of G6PC deletion. c-Myc regulates many aspects of glucose metabolism in cancer, and 75% of GSD1a patients eventually develop hepatic adenomas (HCAs) and hepatocellular carcinomas (HCCs). However, c-Myc activation occurred long before the appearance of malignancy in these mice. We tested if c-Myc potentiates the metabolic anomalies initiated by G6PC deletion. We found modest genetic silencing of c-Myc normalized genes and metabolites related to glycolysis and the pentose phosphate pathway. In both the liver and a hepatocyte cell line, suppressing c-Myc attenuated the accumulation of lactate and urate, despite persistent G6PC deficiency and glycogen accumulation. We found that G6PC deficiency induces a hyperproliferative state in a hepatocyte cell line and premalignant livers, and c-Myc silencing reduced these effects. Finally, we characterized tumors that form in GSD1a as having a strong c-Myc gene signature as well as a low mutational burden relative to sporadic liver cancers, without signs of liver injury or cirrhosis. Overall, our results demonstrate that a monogenic metabolic defect in a human IEM induces a localized oncogenic response in the liver that drives systemic metabolic dysfunction and may contribute to carcinogenesis.","abstract_has_math":false,"creators":["Kelekar, Sherwin Hiren"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Zhu, Hao","Mangelsdorf, David J.","Burgess, Shawn C.","DeBerardinis, Ralph J."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-01-02T21:57:36Z","date_published":"2025-01-02T21:57:36Z","updated_at":"2026-07-24T05:52:22Z","subjects":["Carcinoma, Hepatocellular","Genetic Therapy","Glucose-6-Phosphatase","Glycogen Storage Disease Type I","Liver","Liver Neoplasms","Adenoma, Liver Cell"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1482732347"],"render_values":[{"text":"1482732347","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/10442","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zhu, Hao","Mangelsdorf, David J.","Burgess, Shawn C.","DeBerardinis, Ralph J."]},{"key":"dc:creator","label":"Author","values":["Kelekar, Sherwin Hiren"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-01-02T21:57:36Z","2022-12","December 2022"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Carcinoma, Hepatocellular","Genetic Therapy","Glucose-6-Phosphatase","Glycogen Storage Disease Type I","Liver","Liver Neoplasms","Adenoma, Liver Cell"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/10442","1482732347"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Inborn errors of metabolism (IEMs), which are caused by germline mutations in metabolic enzymes and nutrient transporters, provide an opportunity to observe how discrete metabolic defects cause human disease. Glycogen Storage Disease Type 1a (GSD1a), or von Gierke's disease, is an autosomal recessive IEM caused by defects in Glucose-6-Phosphatase, Catalytic Subunit (G6PC), the terminal enzyme in both glycogenolysis and gluconeogenesis. Fasting hypoglycemia, a prominent symptom of GSD1a, is understandable because of G6PC's role in hepatic glucose output. Other metabolic anomalies in GSD1a, including debilitating lactic acidosis and hyperuricemia, are assumed to be consequences of glucose-6-phosphate accumulation, although the mechanism has not been explored in detail. Late sequela of GSD1a includes the formation of liver adenomas and carcinomas without obvious signs of liver injury or cirrhosis. Here we show that the oncogenic transcription factor c-Myc potentiates metabolic rewiring and drives lactic acidosis and hyperuricemia in a mouse model of GSD1a. Using metabolic profiling and isotope labeling strategies in both in vivo and cultured cell models of GSD1a, we found enhanced use of both glycolysis and the pentose phosphate pathway, which produce precursors to lactate and urate, respectively. Transcriptomic analysis revealed that these metabolic changes were accompanied by increased transcription of genes in both pathways. In addition to stimulating these metabolic pathways, we observed that G6PC deletion stimulates hepatocyte proliferation in culture and in the liver. Overall, the transcriptomic profile of G6PC-deficient livers indicated enhanced expression of c-Myc-responsive genes, and c-Myc itself was markedly induced within two weeks of G6PC deletion. c-Myc regulates many aspects of glucose metabolism in cancer, and 75% of GSD1a patients eventually develop hepatic adenomas (HCAs) and hepatocellular carcinomas (HCCs). However, c-Myc activation occurred long before the appearance of malignancy in these mice. We tested if c-Myc potentiates the metabolic anomalies initiated by G6PC deletion. We found modest genetic silencing of c-Myc normalized genes and metabolites related to glycolysis and the pentose phosphate pathway. In both the liver and a hepatocyte cell line, suppressing c-Myc attenuated the accumulation of lactate and urate, despite persistent G6PC deficiency and glycogen accumulation. We found that G6PC deficiency induces a hyperproliferative state in a hepatocyte cell line and premalignant livers, and c-Myc silencing reduced these effects. Finally, we characterized tumors that form in GSD1a as having a strong c-Myc gene signature as well as a low mutational burden relative to sporadic liver cancers, without signs of liver injury or cirrhosis. Overall, our results demonstrate that a monogenic metabolic defect in a human IEM induces a localized oncogenic response in the liver that drives systemic metabolic dysfunction and may contribute to carcinogenesis."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Glucose-6-Phosphatase in Metabolic Disease and Cancer"]}]}],"canonical_facts":{"dc:contributor":["Zhu, Hao","Mangelsdorf, David J.","Burgess, Shawn C.","DeBerardinis, Ralph J."],"dc:creator":["Kelekar, Sherwin Hiren"],"dc:date":["2025-01-02T21:57:36Z","2022-12","December 2022"],"dc:description":["Inborn errors of metabolism (IEMs), which are caused by germline mutations in metabolic enzymes and nutrient transporters, provide an opportunity to observe how discrete metabolic defects cause human disease. Glycogen Storage Disease Type 1a (GSD1a), or von Gierke's disease, is an autosomal recessive IEM caused by defects in Glucose-6-Phosphatase, Catalytic Subunit (G6PC), the terminal enzyme in both glycogenolysis and gluconeogenesis. Fasting hypoglycemia, a prominent symptom of GSD1a, is understandable because of G6PC's role in hepatic glucose output. Other metabolic anomalies in GSD1a, including debilitating lactic acidosis and hyperuricemia, are assumed to be consequences of glucose-6-phosphate accumulation, although the mechanism has not been explored in detail. Late sequela of GSD1a includes the formation of liver adenomas and carcinomas without obvious signs of liver injury or cirrhosis. Here we show that the oncogenic transcription factor c-Myc potentiates metabolic rewiring and drives lactic acidosis and hyperuricemia in a mouse model of GSD1a. Using metabolic profiling and isotope labeling strategies in both in vivo and cultured cell models of GSD1a, we found enhanced use of both glycolysis and the pentose phosphate pathway, which produce precursors to lactate and urate, respectively. Transcriptomic analysis revealed that these metabolic changes were accompanied by increased transcription of genes in both pathways. In addition to stimulating these metabolic pathways, we observed that G6PC deletion stimulates hepatocyte proliferation in culture and in the liver. Overall, the transcriptomic profile of G6PC-deficient livers indicated enhanced expression of c-Myc-responsive genes, and c-Myc itself was markedly induced within two weeks of G6PC deletion. c-Myc regulates many aspects of glucose metabolism in cancer, and 75% of GSD1a patients eventually develop hepatic adenomas (HCAs) and hepatocellular carcinomas (HCCs). However, c-Myc activation occurred long before the appearance of malignancy in these mice. We tested if c-Myc potentiates the metabolic anomalies initiated by G6PC deletion. We found modest genetic silencing of c-Myc normalized genes and metabolites related to glycolysis and the pentose phosphate pathway. In both the liver and a hepatocyte cell line, suppressing c-Myc attenuated the accumulation of lactate and urate, despite persistent G6PC deficiency and glycogen accumulation. We found that G6PC deficiency induces a hyperproliferative state in a hepatocyte cell line and premalignant livers, and c-Myc silencing reduced these effects. Finally, we characterized tumors that form in GSD1a as having a strong c-Myc gene signature as well as a low mutational burden relative to sporadic liver cancers, without signs of liver injury or cirrhosis. Overall, our results demonstrate that a monogenic metabolic defect in a human IEM induces a localized oncogenic response in the liver that drives systemic metabolic dysfunction and may contribute to carcinogenesis."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/10442","1482732347"],"dc:language":["en"],"dc:subject":["Carcinoma, Hepatocellular","Genetic Therapy","Glucose-6-Phosphatase","Glycogen Storage Disease Type I","Liver","Liver Neoplasms","Adenoma, Liver Cell"],"dc:title":["Glucose-6-Phosphatase in Metabolic Disease and Cancer"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:22Z"}