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Cardiomyocyte-specific loss of diacylglycerol acyltransferase 1 (DGAT1) reproduces the abnormalities in lipids found in severe heart failure.

ABSTRACT: Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis, the conversion of diacylglycerol (DAG) to triglyceride. Dgat1(-/-) mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function, we created cardiomyocyte-specific DGAT1 knock-out (hDgat1(-/-)) mice. hDgat1(-/-) mouse hearts had 95% increased DAG and 85% increased ceramides compared with floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide increased 5-fold in hDgat1(-/-) hearts, and fractional shortening (FS) was reduced. This was associated with increased expression of peroxisome proliferator-activated receptor α and cluster of differentiation 36. We crossed hDgat1(-/-) mice with previously described enterocyte-specific Dgat1 knock-out mice (hiDgat1(-/-)). This corrected the early mortality, improved FS, and reduced cardiac ceramide and DAG content. Treatment of hDgat1(-/-) mice with the glucagon-like peptide 1 receptor agonist exenatide also improved FS and reduced heart DAG and ceramide content. Increased fatty acid uptake into hDgat1(-/-) hearts was normalized by exenatide. Reduced activation of protein kinase Cα (PKCα), which is increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.

SUBMITTER: Liu L

PROVIDER: S-EPMC4207999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Plants and microalgae have the ability to harness sunlight into energy dense molecules such as triacylglycerols (TAGs). TAGs hold great importance for human and animal nutrition, and are also a source for renewable energy. Acyl-CoA-dependent TAG synthesis by diacylglycerol acyltransferases (DGATs) in oilseeds has been well characterized, but how the ectopic introduction of TAG synthesis in vegetative tissues of plants affects metabolism is largely unknown. Here we report the identification and characterization of several Chlamydomonas reinhardtii Diacylglycerol Acyltransferase Type Two (DGTT) enzymes and their use in engineering TAG biosynthesis in plant vegetative tissues. Focusing on DGTT2 we demonstrate that it can accept a broad range of substrates. Production of DGTT2 in Arabidopsis results in distinct seedling phenotypes and accumulation of TAG with very long chain fatty acids (VLCFA), in both seedlings (23.4-fold increase) and in the leaves of soil-grown plants (13.3-fold increase). Levels of surface lipids, such as waxes and cutins, are decreased in DGTT2-producing lines, consistent with a decreased carbon/acyl flux to the surface lipid pathway. Global transcript analysis showed that very few genes had altered expression. Little to no change in the transcripts of wax/cutin pathway genes was observed in response to altered carbon partitioning into TAGs in the leaves suggesting that the supply of acyl groups for surface lipid biosynthesis is not transcriptionally adjusted in the transgenic lines. As an indication that the DGTT2-producing plants are richer in feed value, the generalist herbivore Spodoptera exigua reared on the transgenic plants gained more weight. Apparently, the substrate specificity of DGTT2 from Chlamydomonas when produced in the Arabidopsis cells leads to diversion of carbon from surface compounds in TAGs and enhances the nutritional value of leaves. 4 biological replicates DGTT2 transgenic plants are compared to 4 biological replicates of wild type

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Cardiomyocyte-specific loss of diacylglycerol acyltransferase 1 (DGAT1) reproduces the abnormalities in lipids found in severe heart failure.

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