{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:52:32Z","timestamp":1790689952841,"version":"4.1.0"},"reference-count":45,"publisher":"SAGE Publications","issue":"8","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and glycogenolysis. The accumulation of glucose-6-phosphate leads to increased glycogen and triglyceride levels in the liver. Patients with GSD Ia can develop steatohepatitis, cirrhosis, and increased risk for hepatocellular adenomas and carcinomas. We previously showed that animal models of GSD Ia had defective autophagy and dysfunctional mitochondria. In this study, we examined the effect of VK2809, a liver-specific thyroid hormone receptor \u03b2 agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">G6pc<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      -deficient (GSD Ia) mice were treated with VK2809 or vehicle control by daily intraperitoneal injection for four days. The hepatic triglyceride and glycogen were determined by biochemical assays. Autophagy and mitochondrial biogenesis were measured by Western blotting for key autophagy and mitochondrial markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      VK2809 treatment decreased hepatic mass and triglyceride content in GSD Ia mice. VK2809 stimulated hepatic autophagic flux as evidenced by increased microtubule-associated protein light chain 3-II (LC3B-II), decreased p62 protein levels, activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling, enhancement of protein levels of ATG5-ATG12, and increased lysosomal protein expression. VK2809 also increased the expression of carnitine palmitoyltransferase 1a (CPT1\u03b1) and fibroblast growth factor 21 (\n                      <jats:italic toggle=\"yes\">FGF21<\/jats:italic>\n                      ), as well as mitochondrial biogenesis to promote mitochondrial \u03b2-oxidation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and \u03b2-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2019.0007","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T04:43:41Z","timestamp":1563943421000},"page":"1158-1167","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":60,"title":["A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia"],"prefix":"10.1177","volume":"29","author":[{"given":"Jin","family":"Zhou","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren R.","family":"Waskowicz","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Lim","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, Illinois."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Lian","sequence":"additional","affiliation":[{"name":"Viking Therapeutics, San Diego, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Masamune","sequence":"additional","affiliation":[{"name":"Viking Therapeutics, San Diego, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, Illinois."},{"name":"Department of Pediatrics and Committee on Genetics, The University of Chicago, Chicago, Illinois."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Tran","sequence":"additional","affiliation":[{"name":"Viking Therapeutics, San Diego, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight D.","family":"Koeberl","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina."},{"name":"Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Yen","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore."},{"name":"Department of Medicine, and Duke University Medical Center, Durham, North Carolina."},{"name":"Department of Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,8,19]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2017.12.001"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.189"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-27"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e31816c9013"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.128"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2009.02.003"},{"key":"e_1_3_6_8_2","first-page":"497","article-title":"Hepato-nephro-megalia-glycogenica (Glykogenspeicherkrankheit der Leber und Nieren)","volume":"82","author":"Gierke EV","year":"1929","unstructured":"Gierke EV. 1929. Hepato-nephro-megalia-glycogenica (Glykogenspeicherkrankheit der Leber und Nieren). Beitr Pathol Anat, 82:497\u2013513.","journal-title":"Beitr Pathol Anat"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.10.008"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep44408"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.11.006"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.08.014"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2012.08.005"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.7.15371"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.20046"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07976"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-015-4025-x"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006819"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy343"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26667"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00475"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-108464"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22572"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.014"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-148-11-200806030-00225"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702759104"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.021642"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60580"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1061849"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1632"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aam5855"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1511263"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302774"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2014.18"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-2031"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(08)03612-4"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00244-16"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.10"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.05.002"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2018.07.006"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.07.017"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.75.3.1369"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo-115-2-681"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.11.7.9212078"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.027466"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm4019299"}],"container-title":["Thyroid\u00ae"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/thy.2019.0007","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2019.0007","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2019.0007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:05:42Z","timestamp":1777586742000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/thy.2019.0007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":45,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2019,8]]}},"alternative-id":["10.1089\/thy.2019.0007"],"URL":"https:\/\/doi.org\/10.1089\/thy.2019.0007","relation":{},"ISSN":["1050-7256","1557-9077"],"issn-type":[{"value":"1050-7256","type":"print"},{"value":"1557-9077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8]]}}}