Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα
Robert C. Bauer, … , David J. Steger, Daniel J. Rader
Robert C. Bauer, … , David J. Steger, Daniel J. Rader
Published September 8, 2015
Citation Information: J Clin Invest. 2015;125(10):3809-3818. https://doi.org/10.1172/JCI77095.
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Research Article Metabolism

Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα

Abstract

Variants near the gene TRIB1 are significantly associated with several plasma lipid traits, circulating liver enzymes, and the development of coronary artery disease in humans; however, it is not clear how its protein product tribbles-1 regulates lipid metabolism. Here, we evaluated mice harboring a liver-specific deletion of Trib1 (Trib1_LSKO) to elucidate the role of tribbles-1 in mammalian hepatic lipid metabolism. These mice exhibited increased hepatic triglyceride (TG) content, lipogenic gene transcription, and de novo lipogenesis. Microarray analysis revealed altered transcription of genes that are downstream of the transcription factor C/EBPα, and Trib1_LSKO mice had increased hepatic C/EBPα protein. Hepatic overexpression of C/EBPα in WT mice phenocopied Trib1_LSKO livers, and hepatic knockout of Cebpa in Trib1_LSKO mice revealed that C/EBPα is required for the increased lipogenesis. Using ChIP-Seq, we found that Trib1_LSKO mice had increased DNA-bound C/EBPα near lipogenic genes and the Trib1 gene, which itself was transcriptionally upregulated by C/EBPα overexpression. Together, our results reveal that tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα, which in turn transcriptionally upregulates Trib1. These data suggest an important role for C/EBPα in mediating the lipogenic effects of hepatic Trib1 deletion and provide insight into the association between TRIB1 and plasma lipids, and liver traits in humans.

Authors

Robert C. Bauer, Makoto Sasaki, Daniel M. Cohen, Jian Cui, Mikhaila A. Smith, Batuhan O. Yenilmez, David J. Steger, Daniel J. Rader

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Figure 5

Overexpression of mCebpa in livers of mice phenocopies the increased hepatic TG synthesis observed in Trib1_LSKO mice.

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Overexpression of mCebpa in livers of mice phenocopies the increased hep...
(A) Liver TG content in mice receiving 1 × 1012 AAV_Null or AAV_mCebpa 2 weeks after injection after overnight fast (n = 5). (B) Hepatic lipogenic gene expression in AAV_Null and AAV_mCebpa mice 2 weeks after injection, as measured by TaqMan real-time RT-PCR from 1 μg total RNA. Values are relative expression compared with GAPDH housekeeping gene. (C) De novo lipogenesis in mice from A after overnight fast, refeeding, and fatty acid labeling with [3H]-Acetate. (D) Plasma TC, non-HDL cholesterol, and TG were measured after a 4-hour fast in mice (n = 6) 10 weeks after AAV_Null or AAV_mCebpa injection. Significance was determined in all panels by Student’s t test (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001).