Abstract 20: Tribbles1 (Trib1) is a Novel Regulator of in vivo Hepatic Fatty Acid Lipogenesis in the Mouse.
Tribbles1 (TRIB1) was recently identified in genome-wide association studies as being strongly linked to plasma levels of VLDL, HDL, LDL, and TG as well as coronary artery disease in humans. Previous experiments in mice using AAV-mediated hepatic overexpression of Trib1 confirmed this association, as mice overexpressing Trib1 exhibited reductions of 45% and 57% in plasma total cholesterol (TC) and TG, respectively (Burkhardt et al, 2010). Here we report a Trib1 liver-specific knockout mouse (Trib1_LSKO) created through AAV-mediated delivery of Cre recombinase into adult mice with a floxed version of Trib1. Four weeks after infection, Trib1_LSKO mice exhibited 21% and 70% increases in TC and TG, respectively (p=0.01 and 0.02), as compared to floxed Trib1 littermates infected with null virus (Controls). Trib1_LSKO animals also exhibited a 25% increase in liver weight (p<0.01), and histological analysis revealed steatotic livers in LSKO mice. Real-time PCR analysis revealed >2-fold increases in the hepatic transcription of genes involved in fatty acid synthesis in Trib1_LSKO mice as compared to Controls. Examination of hepatic lipids revealed a 78% increase in hepatic TG content (p<0.001) of Trib1_LSKO mouse livers, while no significant change in hepatic cholesterol was observed. When de novo lipogenesis was measured using [3H]-acetate, Trib1_LSKO animals exhibited significantly increased production of TG (3.6-fold, p<0.001), fatty acids (2.2-fold, p=0.02), diacylglycerol (1.8-fold, p<0.01), and phospholipids (2-fold, p=0.05). Microarray analysis of Trib1_LSKO livers compared to Controls revealed greater than 1,600 genes that were significantly altered between the two groups (fold change>1.5, FDR<10%). Pathway analysis suggested that the altered gene set was enriched for genes downstream of C/EBP and C/EBP. Western blot analysis of liver extracts showed increases in both C/EBP and C/EBP levels in Trib1_LSKO mice compared to Controls. In conclusion, Trib1 is a novel regulator of de novo lipogenesis in mice, presumably through the regulation of lipogenic gene transcription. This transcriptional control may be regulated by increased levels of C/EBP and/or C/EBP, or an as yet undetermined target of Trib1.
- © 2013 by American Heart Association, Inc.