| Abstrakt: |
Coronary artery disease (CAD) is the leading cause of death worldwide, and human genetics has proven to be a powerful approach to identify novel physiological pathways and therapeutic targets for this disease. Genetic variants at chromosomal locus 8q24, 40kb from the TRIB1gene, are significantly associated with CAD, as well as with known CAD risk factors: plasma levels of low-density lipoproteins (LDL) and triglyceride rich lipoproteins. We showed that hepatic specific Trib1deficiency (Trib1LSKO) increases plasma lipid, lipogenesis and hepatic steatosis in mice. TRIB1encodes a pseudokinase protein that targets the transcription factor CEBP? for proteosomal degradation. We have shown that increased lipogenesis and hepatic steatosis in Trib1LSKO mice are attributable to increased protein levels of Cebp?, however, its role in regulating plasma lipids was unclear. Here, we show that Cebp?hepatic deletion reduces plasma lipid levels, implicating Cebp?in their regulation. Until now, the physiological mechanism by which Trib1regulates plasma lipids was unknown. Plasma lipid levels are highly regulated by the rates of secretion from the liver and intestines, triglyceride hydrolysis, and hepatic LDL receptor (LDLR) mediated clearance. Here we show that Trib1LSKO mice exhibit decreased LDLR mRNA and protein expression, and consequently have decreased LDL-ApoB clearance compared to control mice. To test the dependence of the Trib1LSKO plasma lipid phenotype on LDLR, we crossed the floxed Trib1allele onto an LDLR KO background. Surprisingly, in the absence of LDLR, deleting Trib1further increased plasma lipids compared to LDLR KO mice with normal Trib1function, despite the fact that both groups of mice had comparable LDL-ApoB kinetics. Moreover, we performed newly synthesized ApoB secretion experiments comparing Trib1LSKO to control mice and showed that Trib1LSKO mice secrete more ApoB-100 containing lipoprotein than control mice. Overall, this demonstrates that Trib1modulates ApoB catabolism through LDLR dependent mechanisms and regulates steady state plasma lipids by regulating ApoB production. |
