Abstract 20194: DGAT1 Deficiency Decreases Heart PPAR Expression and Causes Hypertrophy
Diacylglycerol acyl (DAG) transferase 1 (Dgat1) knockout (-/-) mice are resistant to high fat-induced obesity and insulin resistance. However, DGAT1 converts DAG to triglyceride and its overexpression in skeletal muscle and heart reduces the content of the potential toxic lipids, DAG and ceramide, leading to concerns that DGAT1 inhibition could lead to cardiac dysfunction. The effects of DGAT1 loss on cardiac lipids and function are not clear. We studied chronic and acute loss of DGAT1 using Dgat1-/- mice and chemical inhibition using a small molecule DGAT1 inhibitor. Dgat1-/- mice had dramatically reduced expression of PPARs and fatty acid oxidation genes as well as PDK4, CPT1 and ATGL. Dgat1-/- mice had larger hearts; mass was increased ∼30% and this was associated with greater P-AKT (183% increase in Dgat-/- mice, P<0.05) and P-mTOR (126% increase in Dgat-/- mice, P<0.05) proteins. Cardiac function assessed by echocardiography was normal and the mice exercised normally. Surprisingly, tissue levels of DAG and ceramide were reduced about 20%; this correlated with reduced expression of PPARα (38±17% of WT, P<0.05), δ (44±21% of WT, P<0.05) and γ (28±11% of WT, P<0.01) and the lipid uptake genes CD36 (43±21% of WT, P<0.05) and LpL (34±14% of WT, P<0.05), and increased heart glucose uptake. Treatment of control mice with a single dose of DGAT1 inhibitor also led to striking reductions in PPARs, lipid uptake, and fatty acid oxidation genes by 8 hours, without increases of ceramides and DAG. The suppression of PPARs and fatty acid oxidation genes in Dgat-/- mice was not reversible by treatment with either a PPARα agonist (WY14643) or a PPARγ agonist (rosiglitazone). Acute inhibition of DGAT1 had a similar effect on cardiac genes in cardiomyocyte-like AC16 cells and prevented the PPAR activation that normally accompanies treatment with palmitic acid. Thus, loss of DGAT1 downregulated PPARs, lipid uptake, and oxidation genes, and produced cardiac hypertrophy, but did NOT lead to toxicity.
- © 2010 by American Heart Association, Inc.