Abstract 19704: Tribbles Homolog-1 (Trib1) Deficiency Promotes Hyperlipidemia, Inflammation and Atherosclerosis in Mice Lacking the LDL-Receptor

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A19704
• Main Authors: Arndt, Lilli, Moos, Doreen, Dokas, Janine, Thiery, Joachim, Breslow, Jan L, Burkhardt, Ralph
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11.11.2016
• ISSN: 0009-7322

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 (Trib1Ldlr) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol). At 20 weeks of age, Trib1Ldlr mice exhibited 7.4-fold larger (457763 vs. 62127 μm, p<0.0001) and more advanced atherosclerotic lesions at the aortic root as compared to Trib1Ldlr littermate controls. Further, we observed significantly elevated plasma total cholesterol (TC) and triglyceride (TG) levels in Trib1Ldlr mice (TC1024 vs. 609mg/dL, p<0.0001; TG360 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 Trib1Ldlr mice. Hepatic inflammation was corroborated by histological analysis, revealing infiltration of inflammatory cell clusters and higher expression of macrophage marker CD68 in livers of Trib1Ldlr 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 Trib1Ldlr 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.