Abstract 21720: Tribbles Homolog-1 (Trib1) Gene Deficiency Causes Mixed Hyperlipidemia in Mice by Increasing Hepatic Lipogenesis and VLDL Production
Recent genome-wide association studies in humans have identified a novel genetic locus at chromosome 8q24 near the TRIB1gene to be associated with plasma cholesterol, triglycerides (TG) and risk for myocardial infarction. Using Trib1 deficient mice (trib1-/-) we investigated if Trib1 is functionally involved in lipid metabolism and explored potential underlying mechanisms. Trib1-/- mice (n=8) and wild-type littermates (n=13) were kept on a standard chow diet and phenotyped at 8 weeks of age. Plasma cholesterol and TG were significantly elevated in trib1-/- mice as compared to controls (Chol: 119.6 vs. 77.4 mg/dL, p<0.001; TG: 76.35 vs. 54.17 mg/dL, p<0.01). Analysis of plasma lipoproteins showed that the elevation of plasma cholesterol in trib1-/- mice was due to increased VLDL-cholesterol (7.58 vs 2.87 mg/dL, p=0.01) and LDL-cholesterol (37.85 vs. 15.14 mg/dL, p<0.001) and elevation of plasma TG was due to increased VLDL-TG (30.98 vs. 15.9 mg/dL, p<0.001). Concomitantly, we observed a 33% increase (p=0.03) in VLDL-TG production in trib1-/- mice. Microarray analysis of hepatic gene expression showed upregulation of genes involved in hepatic lipogenesis in trib1-/- mice, which was confirmed by qPCR: acetyl-CoA carboxylase (2.36-fold, p<0.01), fatty acid synthase (3.05-fold, p=0.03) and stearoyl-CoA desaturase 1 (1.96-fold, p<0.01). Further, using geneset enrichment analysis, we identified promoter binding motifs for C/EBPβ, a transcription factor associated with lipogenesis, as enriched in genes upregulated in trib1-/- livers. We also detected increased nuclear abundance of the C/EBPβ liver-enriched activator protein (LAP) in livers of trib1-/- mice. Finally we demonstrate that the trib1 protein localizes to the nucleus of hepatocytes and that its expression in HepG2 cells correlated functionally with changes in hepatic triglyceride synthesis. In conclusion, our studies demonstrate that genetic deficiency of Trib1 causes mixed hyperlipidemia in mice by increasing hepatic lipogenesis and VLDL secretion through a mechanism potentially involving the transcription factor C/EBPβ. Additional functional studies are necessary to understand the precise molecular mechanism by which trib1 regulates the transcription of lipogenic genes.
- © 2010 by American Heart Association, Inc.