Abstract
IntroductionThe dys-regulation of multiple physiological systems, with obesity as a risk factor, contributes to various facets of metabolic diseases including diabetes, hypertension and cardiovascular disease. Trib-3 plays a role in many of these metabolic processes, including insulin resistance. The aim of this study was to understand the mechanisms by which trib-3 affects metabolism leading to obesity.MethodsTrib-3-/- mouse was created using a gene-trap system thereby disrupting transcription of the Trib-3 mRNA. Microarray analysis was performed on Trib-3-/- and wild type littermate liver tissues. IPA software package was used for bioinformatics analysis of the data. qPCR and Western blots were carried out to substantiate the microarray findings. Tissue morphology was verified by histomorphometric analysis and triglyceride content was quantified using ELISA.ResultsMale Trib-3-/- mice are obese with elevated plasma levels of vLDL and cholesterol. These knockout mice also exert a fatty liver phenotype. Microarray analysis revealed the dysregulation of multiple metabolic genes including SAA1, PPAR-α and FCER1G with up-to 3x fold change. Western blots have confirmed reduced levels of PPAR-α (***P < 0.0001, 50% reduction, n = 5), CEBPα (*P < 0.01, 30% reduction, n = 5) and AKT (***p < 0.0001, 70% reduction, n = 5) in the Trib-3-/- mice compared to wildtype mice. In addition, we have detected a concurrent increase in GLUT2 levels in TRIB3 deficient livers. ConclusionA reduction in lipid-sensor PPARα suggest a molecular mechanisms for ‘mis-handling’ of fatty acids, causing accumulation in the liver leading to a dysfunctional, fatty liver. Our findings suggest that trib-3 plays an important part in regulating hepatic lipid homeostasis.