Dataset Information

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 | 2014 Oct

REPOSITORIES: biostudies-literature

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

Liu Li L Trent Chad M CM Fang Xiang X Son Ni-Huiping NH Jiang HongFeng H Blaner William S WS Hu Yunying Y Yin Yu-Xin YX Farese Robert V RV Homma Shunichi S Turnbull Andrew V AV Eriksson Jan W JW Hu Shi-Lian SL Ginsberg Henry N HN Huang Li-Shin LS Goldberg Ira J IJ

The Journal of biological chemistry 20140825 43

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 ...[more]

PMID: 25157099

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Project description:BackgroundOil in the form of triacylglycerols (TAGs) is quantitatively the most important storage form of energy for eukaryotic cells. Diacylglycerol acyltransferase (DGAT) is considered the rate-limiting enzyme for TAG accumulation. Chlorella, a unicellular eukaryotic green alga, has attracted much attention as a potential feedstock for renewable energy production. However, the function of DGAT1 in Chlorella has not been reported.ResultsA full-length cDNA encoding a putative diacylglycerol acyltransferase 1 (DGAT1, EC 2.3.1.20) was obtained from Chlorella ellipsoidea. The 2,142 bp open reading frame of this cDNA, designated CeDGAT1, encodes a protein of 713 amino acids showing no more than 40% identity with DGAT1s of higher plants. Transcript analysis showed that the expression level of CeDGAT1 markedly increased under nitrogen starvation, which led to significant triacylglycerol (TAG) accumulation. CeDGAT1 activity was confirmed in the yeast quadruple mutant strain H1246 by restoring its ability to produce TAG. Upon expression of CeDGAT1, the total fatty acid content in wild-type yeast (INVSc1) increased by 142%, significantly higher than that transformed with DGAT1s from higher plants, including even the oil crop soybean. The over-expression of CeDGAT1 under the NOS promoter in wild-type Arabidopsis thaliana and Brassica napus var. Westar significantly increased the oil content by 8-37% and 12-18% and the average 1,000-seed weight by 9-15% and 6-29%, respectively, but did not alter the fatty acid composition of the seed oil. The net increase in the 1,000-seed total lipid content was up to 25-50% in both transgenic Arabidopsis and B. napus.ConclusionsWe identified a gene encoding DGAT1 in C. ellipsoidea and confirmed that it plays an important role in TAG accumulation. This is the first functional analysis of DGAT1 in Chlorella. This information is important for understanding lipid synthesis and accumulation in Chlorella and for genetic engineering to enhance oil production in microalgae and oil plants.

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

Dataset Information

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

Publications

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

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