GSE158815
Trib1 regulates mouse LDL metabolism through Cebpa-mediated regulation of the LDL receptor in hepatocytes.
The Tribbles homolog 1 protein (TRIB1), encoded by the gene TRIB1, has been identified by genome-wide association studies (GWAS) as likely to be causal of a remarkable number of cardiometabolic traits, including plasma lipids, hepatic steatosis, adiponectin levels, and coronary artery disease. In its best-known function, Tribbles 1 interacts with the ubiquitin ligate COP1 protein to target the transcription factors CCAAT/enhancer-binding protein alpha and beta (CEBP a/b) for proteasomal degradation. We have previously published that specific Trib1 deletion in mice increased de novo lipogenesis, hepatic steatosis, and plasma triglycerides, attributable at least in part to increased protein levels of hepatic Cebpa. However, the mechanism by which Trib1 regulates plasma lipids and specifically LDL-C metabolism remained unknown. In this experiment our aim was to identify possible molecular interactions by which hepatic Trib1 regulates specifically LDL-C metabolism dependently of Cebpa expression.  To do this, we compared total gene expression in livers of wild type mice, Trib1, Cebpa and Trib1;Cebpa hepatic deleted mice.  Gene expression data was then used in Ingenuity Pathway analysis to identify upstream transcription factors that might be responsible for the gene expression changes observed. Overall design: Four groups of mice were used for this experiment: wild type Trib1 Flox/Flox, Cebpa Flox/Flox and Trib1;Cebpa Flox/Flox. The mice were 20-21 weeks of age when injected with adeno associated virus (AAV) encoding Cre recombinase (AAV_Cre). The mice were injected in 2 different cohorts with a total n=6 mice per group. Mice were euthanized at 4-week post injection of AAV, and RNA collected from whole liver tissue.