PMID- 31337282 OWN - NLM STAT- MEDLINE DCOM- 20201021 LR - 20201021 IS - 1557-9077 (Electronic) IS - 1050-7256 (Print) IS - 1050-7256 (Linking) VI - 29 IP - 8 DP - 2019 Aug TI - A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia. PG - 1158-1167 LID - 10.1089/thy.2019.0007 [doi] AB - Background: 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 beta agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia. Methods:G6pc(-/-)-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. Results: 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 (CPT1alpha) and fibroblast growth factor 21 (FGF21), as well as mitochondrial biogenesis to promote mitochondrial beta-oxidation. Conclusions: In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and beta-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease. FAU - Zhou, Jin AU - Zhou J AD - 1Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore. FAU - Waskowicz, Lauren R AU - Waskowicz LR AD - 2Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina. FAU - Lim, Andrea AU - Lim A AD - 1Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore. FAU - Liao, Xiao-Hui AU - Liao XH AD - 3Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Lian, Brian AU - Lian B AD - 4Viking Therapeutics, San Diego, California. FAU - Masamune, Hiroko AU - Masamune H AD - 4Viking Therapeutics, San Diego, California. FAU - Refetoff, Samuel AU - Refetoff S AD - 3Department of Medicine, The University of Chicago, Chicago, Illinois. AD - 5Department of Pediatrics and Committee on Genetics, The University of Chicago, Chicago, Illinois. FAU - Tran, Brian AU - Tran B AD - 4Viking Therapeutics, San Diego, California. FAU - Koeberl, Dwight D AU - Koeberl DD AD - 2Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina. AD - 6Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. FAU - Yen, Paul M AU - Yen PM AD - 1Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore. AD - 7Department of Medicine, and Duke University Medical Center, Durham, North Carolina. AD - 8Department of Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina. LA - eng GR - R01 DK015070/DK/NIDDK NIH HHS/United States GR - R01 DK105434/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Thyroid JT - Thyroid : official journal of the American Thyroid Association JID - 9104317 RN - 0 (2-((3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl)-4-(3-chlorophenyl)-2-oxido(1,3,2)dioxaphosphonane) RN - 0 (Fatty Acids) RN - 0 (Organophosphonates) RN - 0 (Thyroid Hormone Receptors beta) RN - 0 (Triglycerides) RN - 9005-79-2 (Glycogen) RN - EC 3.1.3.9 (Glucose-6-Phosphatase) RN - Hepatorenal form of glycogen storage disease SB - IM MH - Animals MH - Autophagy/*drug effects MH - Disease Models, Animal MH - Fatty Acids/metabolism MH - Fatty Liver/*metabolism MH - Glucose-6-Phosphatase/genetics MH - Glycogen/metabolism MH - Glycogen Storage Disease Type I/genetics/*metabolism MH - Liver/*drug effects/metabolism MH - Mice MH - Mice, Knockout MH - Mitochondria, Liver/*drug effects/metabolism MH - Organelle Biogenesis MH - Organophosphonates/*pharmacology MH - Oxidation-Reduction MH - Thyroid Hormone Receptors beta/*agonists MH - Triglycerides/metabolism PMC - PMC6707038 OTO - NOTNLM OT - VK2809 OT - autophagy OT - glycogen storage disease type Ia OT - lipid metabolism OT - mitochondrial biogenesis OT - thyroid hormone mimetic COIS- D.D.K. served on a data and safety monitoring board for Baxter International. He was supported by a grant from Roivant Rare Diseases. He received an honorarium and grant support in the past from Genzyme Sanofi. He holds equity in Actus Therapeutics. D.D.K. and P.M.Y. have developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and the Duke University may benefit financially. EDAT- 2019/07/25 06:00 MHDA- 2020/10/22 06:00 PMCR- 2020/08/01 CRDT- 2019/07/25 06:00 PHST- 2019/07/25 06:00 [pubmed] PHST- 2020/10/22 06:00 [medline] PHST- 2019/07/25 06:00 [entrez] PHST- 2020/08/01 00:00 [pmc-release] AID - 10.1089/thy.2019.0007 [pii] AID - 10.1089/thy.2019.0007 [doi] PST - ppublish SO - Thyroid. 2019 Aug;29(8):1158-1167. doi: 10.1089/thy.2019.0007.