Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.molmet.2021.101266
Title: Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression
Authors: Bruinstroop, E 
Zhou, J 
Tripathi, M 
Yau, WW 
Boelen, A
Singh, BK 
Yen, PM 
Keywords: Deiodinase
Liver
NAFLD
NASH
Steatosis
Thyroid
Animals
Cells, Cultured
Hepatocytes
Iodide Peroxidase
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Non-alcoholic Fatty Liver Disease
Issue Date: 1-Nov-2021
Publisher: Elsevier BV
Citation: Bruinstroop, E, Zhou, J, Tripathi, M, Yau, WW, Boelen, A, Singh, BK, Yen, PM (2021-11-01). Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression. Molecular Metabolism 53 : 101266-. ScholarBank@NUS Repository. https://doi.org/10.1016/j.molmet.2021.101266
Abstract: 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.
Source Title: Molecular Metabolism
URI: https://scholarbank.nus.edu.sg/handle/10635/226739
ISSN: 22128778
DOI: 10.1016/j.molmet.2021.101266
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