Functional Characterization of TRIB1, a Gene Associated with Multiple Cardiometabolic Traits

Genetic variants near the TRIB1 gene are significantly associated with plasma lipid traits and coronary artery disease. While data suggest TRIB1 is the causal gene for these traits, the mechanisms by which TRIB1 affects plasma lipids are not fully understood. In these studies, I sought to elucidate the physiological and molecular mechanism by which TRIB1 affects plasma lipids. Using a Trib1 hepatocyte specific deletion mouse model (Trib1Δhep), I demonstrated that Trib1Δhep mice have significantly increased plasma total cholesterol, HDL cholesterol, non-HDL cholesterol, LDL cholesterol and apoB protein levels, as well as impaired postprandial triglyceride clearance. I also showed that Trib1Δhep mice have markedly delayed catabolism of LDL-apoB and VLDL-apoB due to significantly decreased Ldlr mRNA and protein expression. Since TRIB1’s most studied molecular function is the COP1-mediated ubiquitination and proteasomal degradation the transcription factor CEBPa, I explored if this interaction is responsible for TRIB1 effects on plasma lipids and LDLR. I demonstrated that hepatic deletion of Cebpa in Trib1Δhep mice eliminated the effects on plasma lipids, apoB catabolism and hepatic LDLR regulation. Additionally, I identified the Activating Transcription Factor 3 (Atf3) as a possible novel mechanism linking TRIB1 to the regulation of LDLR in a CEBPa dependent manner. We also discovered that Trib1 whole body deletion (Trib1 KO) on a pure C57BL/6 background leads to a highly penetrant neonatal lethal phenotype, with less than 5% of Trib1 KO mice making to weaning stages. Our studies determined that Trib1 KO perish between day 0 and day 1 after birth likely due to severely low blood glucose levels. I also determined that about adult Trib1 KO mouse have decreased fasting glucose levels, and improved glucose and insulin tolerance. Overall, my studies stablish Trib1 and its regulation of CEBPa as critical factors in the regulation of multiple metabolic pathways affecting plasma lipids, as well as novel regulators of the LDLR and glucose metabolism