Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα.
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.
Robert C
RC
Bauer
Makoto
M
Sasaki
Daniel M
DM
Cohen
Jian
J
Cui
Mikhaila A
MA
Smith
Batuhan O
BO
Yenilmez
David J
DJ
Steger
Daniel J
DJ
Rader
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006949:Hyperlipidemias / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional; D046888:Tissue Array Analysis; D019076:Transgenes; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C523598:Trib1 protein, mouse; D014280:Triglycerides; D004247:DNA; D000410:Alanine Transaminase; D017346:Protein Serine-Threonine Kinases