Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression
Objective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very pr...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821001113 |
| _version_ | 1818401206641360896 |
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| author | Eveline Bruinstroop Jin Zhou Madhulika Tripathi Winifred W. Yau Anita Boelen Brijesh Kumar Singh Paul M. Yen |
| author_facet | Eveline Bruinstroop Jin Zhou Madhulika Tripathi Winifred W. Yau Anita Boelen Brijesh Kumar Singh Paul M. Yen |
| author_sort | Eveline Bruinstroop |
| collection | DOAJ |
| description | Objective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD. Methods: We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured. Results: Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. Conclusion: Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression. |
| first_indexed | 2024-12-14T07:48:47Z |
| format | Article |
| id | doaj.art-d879531f2fef46d28ca34500556eedee |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-14T07:48:47Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-d879531f2fef46d28ca34500556eedee2022-12-21T23:10:48ZengElsevierMolecular Metabolism2212-87782021-11-0153101266Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progressionEveline Bruinstroop0Jin Zhou1Madhulika Tripathi2Winifred W. Yau3Anita Boelen4Brijesh Kumar Singh5Paul M. Yen6Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Department of Endocrinology & Metabolism, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Corresponding author. Department of Endocrinology & Metabolism, K2-283, Amsterdam UMC, locatie AMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, SingaporeLaboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, SingaporeLaboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, SingaporeEndocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsLaboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, SingaporeLaboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Duke Molecular Physiology Institute, Duke University School of Medicine, 300 N Duke St, Durham, NC 27701, USA; Endocrinology, Diabetes, and Metabolism Division, Duke University School of Medicine, 300 N Duke St, Durham, NC 27701, USAObjective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD. Methods: We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured. Results: Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. Conclusion: Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression.http://www.sciencedirect.com/science/article/pii/S2212877821001113LiverSteatosisThyroidNAFLDDeiodinaseNASH |
| spellingShingle | Eveline Bruinstroop Jin Zhou Madhulika Tripathi Winifred W. Yau Anita Boelen Brijesh Kumar Singh Paul M. Yen Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression Molecular Metabolism Liver Steatosis Thyroid NAFLD Deiodinase NASH |
| title | Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression |
| title_full | Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression |
| title_fullStr | Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression |
| title_full_unstemmed | Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression |
| title_short | Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression |
| title_sort | early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during nafld progression |
| topic | Liver Steatosis Thyroid NAFLD Deiodinase NASH |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821001113 |
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