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 7

Trib1_LSKO mice have increased C/EBPα occupancy near lipogenic genes.

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Trib1_LSKO mice have increased C/EBPα occupancy near lipogenic genes. (A...
(A) Pie chart of all C/EBPα binding sites identified in liver by ChIP-seq showing the number of sites that were unchanged (constitutive), increased or decreased in Trib1_LSKO mice compared with Trib1_fl/fl mice. Density heat maps (lower panel) of raw sequence tags at regions differentially occupied by C/EBPα in Trib1_LSKO mice are shown for Trib1_fl/fl, Trib1_LSKO, AAV_Null, and AAV_mCebpa mice. (B) HOMER de novo motif analysis of constitutive and differential C/EBPα-binding sites in Trib1_LSKO mice. (C) Relationship of gene expression to C/EBPα occupancy. Left panel shows the relative expression of all genes in the microarray ordered from highest to lowest fold-change in Trib1_LSKO vs. fl/fl control. Right heat map depicts C/EBPα occupancy in Trib1_fl/fl and Trib1_LSKO mice at sites within 100 kb of the TSS. (D) Heat map of differential C/EBPα binding sites within 100 kb of the TSS for genes involved in hepatic lipogenesis. The number of C/EBPα sites and the microarray fold change are indicated on the right for each gene.