Trib1 Deficiency Promotes Hyperlipidemia, Inflammation, and Atherosclerosis in LDL Receptor Knockout Mice

Abstract

BACKGROUND: Genetic variants at the TRIB1 gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. Here, we analyzed the consequences of Trib1 deficiency on lipid metabolism and atherosclerotic lesion formation in atherosclerosis-susceptible Ldlr −/ − . METHODS: 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 and 4.3% fat) until 20 weeks of age. RESULTS: Trib1 −/− Ldlr −/− mice had profoundly larger (5.8-fold) and more advanced atherosclerotic lesions at the aortic root as compared with Trib1 +/+ Ldlr −/− controls. Further, we observed significantly elevated plasma total cholesterol and triglyceride levels in Trib1 −/− Ldlr −/− mice, resulting from higher VLDL (very-low-density lipoprotein) secretion. Lipidomics analysis revealed that loss of Trib1 altered hepatic lipid composition, including the accumulation of cholesterol and proinflammatory ceramide species, which was accompanied by signs of hepatic inflammation and injury. Concomitantly, we detected higher plasma levels of IL (interleukin)-6 and LCN2 (lipocalin 2), suggesting increased systemic inflammation in Trib1 −/− Ldlr −/− mice. Hepatic transcriptome analysis demonstrated significant upregulation of key genes controlling lipid metabolism and inflammation in Trib1 −/− Ldlr −/− mice. Further experiments suggested that these effects may be mediated through pathways involving a C/EPB-PPARγ axis and JNK signaling. CONCLUSIONS: We provide experimental evidence that Trib1 deficiency promotes atherosclerotic lesion formation in a complex manner that includes the modulation of lipid metabolism and inflammation.

“Oh, Dear We Are in Tribble”: An Overview of the Oncogenic Functions of Tribbles 1

“…Increased TRIB1 gene expression is encountered in the coronary arteries of patients with ischemic heart disease [38]. Genetic deletion of TRIB1 promotes atherosclerosis in mice, which is accompanied by pronounced hyperlipidemia and hepatic and systemic inflammation [82]. However, lack of TRIB1 in myeloid cells decreases early atheroma formation and reduces atherosclerosis burden in mouse models [83].…”