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Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis.

Publication ,  Journal Article
Zhou, J; Tripathi, M; Ho, JP; Widjaja, AA; Shekeran, SG; Camat, MD; James, A; Wu, Y; Ching, J; Kovalik, J-P; Lim, K-H; Cook, SA; Bay, B-H ...
Published in: Thyroid
June 2022

Background: Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, lobular inflammation, and fibrosis. Thyroid hormone (TH) reduces steatosis; however, the therapeutic effect of TH on NASH-associated inflammation and fibrosis is not known. This study examined the therapeutic effect of TH on hepatic inflammation and fibrosis during NASH and investigated THs molecular actions on autophagy and mitochondrial biogenesis. Methods: HepG2-TRβ cells were treated with bovine serum albumin-conjugated palmitic acid (PA) to mimic lipotoxic conditions in vitro. Mice with NASH were established by feeding C57BL/6J mice Western diet with 15% fructose in drinking water for 16 weeks. These mice were administered triiodothyronine (T3)/thyroxine (T4) supplemented in drinking water for the next eight weeks. Results: In cultured HepG2-TRβ cells, TH treatment increased mitochondrial respiration and fatty acid oxidation under basal and PA-treated conditions, as well as decreased lipopolysaccharides and PA-stimulated inflammatory and fibrotic responses. In a dietary mouse model of NASH, TH administration decreased hepatic triglyceride content (3.19 ± 0.68 vs. 8.04 ± 0.42 mM/g liver) and hydroxyproline (1.44 ± 0.07 vs. 2.58 ± 0.30 mg/g liver) when compared with mice with untreated NASH. Metabolomics profiling of lipid metabolites showed that mice with NASH had increased triacylglycerol, diacylglycerol, monoacylglycerol, and hepatic cholesterol esters species, and these lipid species were decreased by TH treatment. Mice with NASH also showed decreased autophagic degradation as evidenced by decreased transcription Factor EB and lysosomal protease expression, and accumulation of LC3B-II and p62. TH treatment restored the level of lysosomal proteins and resolved the accumulation of LC3B-II and p62. Impaired mitochondrial biogenesis was also restored by TH. The simultaneous restoration of autophagy and mitochondrial biogenesis by TH increased β-oxidation of fatty acids. Additionally, the elevated oxidative stress and inflammasome activation in NASH liver were also decreased by TH. Conclusions: In a mouse model of NASH, TH restored autophagy and mitochondrial biogenesis to increase β-oxidation of fatty acids and to reduce lipotoxicity, oxidative stress, hepatic inflammation, and fibrosis. Activating thyroid hormone receptor in the liver may represent an effective strategy for NASH treatment.

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Published In

Thyroid

DOI

EISSN

1557-9077

Publication Date

June 2022

Volume

32

Issue

6

Start / End Page

725 / 738

Location

United States

Related Subject Headings

  • Triglycerides
  • Thyroid Hormones
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Mice
  • Liver
  • Inflammation
  • Humans
  • Fibrosis
  • Fatty Acids
 

Citation

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Zhou, J., Tripathi, M., Ho, J. P., Widjaja, A. A., Shekeran, S. G., Camat, M. D., … Yen, P. M. (2022). Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis. Thyroid, 32(6), 725–738. https://doi.org/10.1089/thy.2021.0621
Zhou, Jin, Madhulika Tripathi, Jia Pei Ho, Anissa Anindya Widjaja, Shamini Guna Shekeran, Macalinao Dominique Camat, Anne James, et al. “Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis.Thyroid 32, no. 6 (June 2022): 725–38. https://doi.org/10.1089/thy.2021.0621.
Zhou J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Camat MD, et al. Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis. Thyroid. 2022 Jun;32(6):725–38.
Zhou, Jin, et al. “Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis.Thyroid, vol. 32, no. 6, June 2022, pp. 725–38. Pubmed, doi:10.1089/thy.2021.0621.
Zhou J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Camat MD, James A, Wu Y, Ching J, Kovalik J-P, Lim K-H, Cook SA, Bay B-H, Singh BK, Yen PM. Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis. Thyroid. 2022 Jun;32(6):725–738.
Journal cover image

Published In

Thyroid

DOI

EISSN

1557-9077

Publication Date

June 2022

Volume

32

Issue

6

Start / End Page

725 / 738

Location

United States

Related Subject Headings

  • Triglycerides
  • Thyroid Hormones
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Mice
  • Liver
  • Inflammation
  • Humans
  • Fibrosis
  • Fatty Acids