Arndt, Lilli and Hernandez-Resendiz, Ileana and Moos, Doreen and Dokas, Janine and Mueller, Silvana and Jeromin, Franziska and Wagner, Richard and Ceglarek, Uta and Heid, Iris M. and Hoering, Marcus and Liebisch, Gerhard and Stadler, Sonja C. and Burkhardt, Ralph (2023) <i>Trib1</i> Deficiency Promotes Hyperlipidemia, Inflammation, and Atherosclerosis in LDL Receptor Knockout Mice. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 43 (6). pp. 979-994. ISSN 1079-5642, 1524-4636
Full text not available from this repository. (Request a copy)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(-/-) mice. 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 (CCAAT/enhancer binding protein)-PPAR gamma (peroxisome proliferator-activated receptor gamma) axis and JNK (c-Jun N-terminal kinase) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HIGH-THROUGHPUT QUANTIFICATION; REGULATES HEPATIC LIPOGENESIS; LIPOTOXICITY; GENE; ASSOCIATION; CHOLESTEROL; EXPRESSION; SECRETION; TRIBBLES; LOCI; atherosclerosis; cholesterol; inflammation; lipoproteins; triglycerides |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Mar 2024 09:53 |
| Last Modified: | 09 Mar 2024 09:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59302 |
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