Abstract 19704: Tribbles Homolog-1 (Trib1) Deficiency Promotes Hyperlipidemia, Inflammation and Atherosclerosis in Mice Lacking the LDL-Receptor
TRIB1 was recently identified in genome-wide association studies as a novel candidate gene influencing the concentration of plasma lipids and the development of coronary artery disease. The aim of the present study was to analyze the consequences of Trib1-deficiency on lipid metabolism and atherosclerotic lesion formation in atherosclerosis-susceptible LDL-receptor knockout mice (Ldlr-/-).
Trib1-/- mice were crossed onto the Ldlr-/- background to generate double knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol). At 20 weeks of age, Trib1-/-Ldlr-/- mice exhibited 7.4-fold larger (457763 vs. 62127 μm2, p<0.0001) and more advanced atherosclerotic lesions at the aortic root as compared to Trib1+/+Ldlr-/- littermate controls. Further, we observed significantly elevated plasma total cholesterol (TC) and triglyceride (TG) levels in Trib1-/-Ldlr-/- mice (TC: 1024 vs. 609mg/dL, p<0.0001; TG: 360 vs. 136mg/dL, p<0.0001), mainly due to increased VLDL-C (5.0-fold, p<0.0001) and increased VLDL-TG (4.1-fold, p<0.0001). Microarray analysis of hepatic mRNA demonstrated profound up-regulation of key genes controlling lipoprotein synthesis and assembly as well as a pro-inflammatory gene expression signature in Trib1-/-Ldlr-/- mice. Hepatic inflammation was corroborated by histological analysis, revealing infiltration of inflammatory cell clusters and higher expression of macrophage marker CD68 in livers of Trib1-/-Ldlr-/- mice. Concomitantly, plasma levels of Interleukin-6 were 3.6-fold higher (9.9 vs. 2.7 pg/ml; p<0.0001), suggesting an increased systemic inflammatory burden in Trib1-/-Ldlr-/- mice.
In conclusion, we provide experimental evidence for the first time that the novel lipid candidate gene Trib1 modulates atherosclerotic lesion formation. In Ldlr-/- mice, Trib1–deficiency increases plasma VLDL-C and VLDL-TG levels and causes hepatic inflammation, which likely contributes to the exacerbation of atherosclerotic lesion formation. Additional functional studies are necessary to unravel the precise molecular mechanisms by which Trib1 regulates lipoprotein metabolism and inflammation.
Author Disclosures: L. Arndt: None. D. Moos: None. J. Dokas: None. J. Thiery: None. J.L. Breslow: None. R. Burkhardt: None.
- © 2016 by American Heart Association, Inc.