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- Title
Thyroid hormone signaling promotes hepatic lipogenesis through the transcription factor ChREBP.
- Authors
Mendoza, Arturo; Tang, Catherine; Choi, Jinyoung; Acuña, Mariana; Logan, Maya; Martin, Adriana G.; Al-Sowaimel, Lujain; Desai, Bhavna N.; Tenen, Danielle E.; Jacobs, Christopher; Lyubetskaya, Anna; Fu, Yulong; Liu, Hong; Tsai, Linus; Cohen, David E.; Forrest, Douglas; Wilson, Andrew A.; Hollenberg, Anthony N.
- Abstract
Fattening livers with thyroid hormone: Nonalcoholic fatty liver disease can lead to impaired hepatic function and carcinogenesis. Analogs of the thyroid hormone T3 have been suggested as a possible therapy for NAFLD because T3 can promote fatty acid oxidation in the liver. However, T3 can also have the opposite effect on hepatic lipid metabolism, which Mendoza et al. investigated with mice with liver-specific deficiencies on diets that mimicked hypothyroidism or hyperthyroidism. The authors found that T3 enhanced de novo lipogenesis in the liver through the transcription factor ChREBP, which was recruited to the promoters of lipogenic genes by the T3 receptor TRβ1. Mice with a hepatocyte-specific deficiency of ChREBP had decreased hepatic triglyceride amounts in response to T3 treatment. These results suggest that T3 analogs may regulate both the accumulation and removal of lipids in the liver. Thyroid hormone (TH) action is essential for hepatic lipid synthesis and oxidation. Analysis of hepatocyte-specific thyroid receptor β1 (TRβ1) knockout mice confirmed a role for TH in stimulating de novo lipogenesis and fatty acid oxidation through its nuclear receptor. Specifically, TRβ1 and its principal corepressor NCoR1 in hepatocytes repressed de novo lipogenesis, whereas the TH-mediated induction of lipogenic genes depended on the transcription factor ChREBP. Mice with a hepatocyte-specific deficiency in ChREBP lost TH-mediated stimulation of the lipogenic program, which, in turn, impaired the regulation of fatty acid oxidation. TH regulated ChREBP activation and recruitment to DNA, revealing a mechanism by which TH regulates specific signaling pathways. Regulation of the lipogenic pathway by TH through ChREBP was conserved in hepatocytes derived from human induced pluripotent stem cells. These results demonstrate that TH signaling in the liver acts simultaneously to enhance both lipogenesis and fatty acid oxidation.
- Subjects
THYROID hormone regulation; LIPID metabolism; NON-alcoholic fatty liver disease; PLURIPOTENT stem cells; TRANSCRIPTION factors; FATTY acid oxidation; LIPID synthesis; THYROID hormones
- Publication
Science Signaling, 2021, Vol 14, Issue 709, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abh3839