Diacylglycerol acyl transferase 1 overexpression detoxifies cardiac lipids in PPARγ transgenic mice - PubMed (original) (raw)

Diacylglycerol acyl transferase 1 overexpression detoxifies cardiac lipids in PPARγ transgenic mice

Li Liu et al. J Lipid Res. 2012 Aug.

Abstract

Accumulation of excess lipids is associated with heart failure. The effects of transgenic expression of diacylglycerol acyl transferase 1 (DGAT1) in cardiomyocytes is controversial. We explored whether mice expressing DGAT1 via the myosin heavy chain (MHC) promoter develop heart dysfunction with aging or after crossing with mice over expressing peroxisome proliferator-activated receptor γ (PPARγ) in the heart. MHC-DGAT1 transgenic mice had increased heart triglyceride but no evidence of heart dysfunction, even up to age 12 months. The MHC-DGAT1 transgene improved heart dysfunction and survival of MHC-PPARγ-expressing transgenic mice. Both diacylglycerol and ceramide levels in the heart were reduced by this cross, as were the levels of several mRNAs of genes involved in lipid metabolism. There were fewer large lipid droplets in MHC-DGAT1×MHC-PPARγ mice compared with MHC-PPARγ, but total lipid content was not changed. Therefore, overexpression of DGAT1 is not toxic to the heart but reduces levels of toxic lipids and improves lipotoxic cardiomyopathy. Moreover, the beneficial effects of DGAT1 illustrate the interrelationship of several lipid metabolic pathways and the difficulty of assigning benefit to an isolated change in one potentially toxic lipid species.

PubMed Disclaimer

Figures

Fig. 1.

Fig. 1.

Survival rate and heart weight in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice. (A) Male and female MHC-PPARγ mouse survival was increased by the MHC-DGAT1 transgene (Log-rank test,P ≤ 0.01). (B) Male and female heart weights were significantly increased in MHC-PPARγ and MHC-DGAT1×MHC-PPARγ mice (one-way ANOVA, *P < 0.05, **P < 0.01 of LSD_t_-test).

Fig. 2.

Fig. 2.

Lipid content in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice. (A) TG was increased in MHC-PPARγ and MHC-DGAT1×MHC-PPARγ mice compared with their WT litter mates (n = 5–6, one-way ANOVA, **P < 0.01, ***P < 0.001 of LSD_t_-test). (B–D) Increased FFA, DAG, and ceramide levels in MHC-PPARγ mice were reduced by MHC-DGAT1 transgene (n = 5–6, one-way ANOVA, *P < 0.05, **P < 0.01 of LSD_t_-test).

Fig. 3.

Fig. 3.

Cardiac function in WT, MHC-DGAT1, MHC-PPARγ, MHC-DGAT1×MHC-PPARγ. (A) Fraction shorting (FS), (B) left ventricular systolic dimension (LVDs), and (C) left ventricular diastolic dimension (LVDd) (n = 5–6, one-way ANOVA, *P < 0.05 of LSD _t_-test) are shown. (D) Representative photographs of echocardiograms.

Fig. 4.

Fig. 4.

Lipid droplet changes in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice. (A) Electron microscopy pictures of lipid droplets, (B) lipid droplet numbers per area (n = 3, one-way ANOVA, *P < 0.05, **P< 0.01 of LSD _t_-test), and (C) lipid droplet size distribution in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice.

Fig. 4.

Fig. 4.

Lipid droplet changes in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice. (A) Electron microscopy pictures of lipid droplets, (B) lipid droplet numbers per area (n = 3, one-way ANOVA, *P < 0.05, **P< 0.01 of LSD _t_-test), and (C) lipid droplet size distribution in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice.

Fig. 5.

Fig. 5.

Western blot of PKCs, Glut1, and insulin signaling pathways in WT, MHC-DGAT1, MHC-PPARγ, and MHC-DGAT1×MHC-PPARγ mice. A: Membrane associated PKCα and PKCδ were increased in MHC-PPARγ cardiac muscle but only PKCα was down-regulated in MHC-DGAT1XPPARγ mice. B: The MHC-DGAT1 transgene also decreased PDK4 protein (***P<0.001) and elevated membrane and cytosol Glut1, which was significantly decreased in MHC-PPARγ cardiac muscle. C: P-IRS1 and P-AKT levels in hearts.

Fig. 6.

Fig. 6.

Cardiac function in 12-month-old WT and MHC-DGAT1 mice. (A) Representative photographs of echocardiograms of 12-month-old WT and MHC-DGAT1 mice, and (B) FS, LVDd, and LVDd of these mice (n = 6 and 8). (C) Two representative collagen staining pictures of mice.

References

    1. Park T. S., Yamashita H., Blaner W. S., Goldberg I. J. 2007. Lipids in the heart: a source of fuel and a source of toxins. Curr. Opin. Lipidol. 18: 277–282 - PubMed
    1. Drosatos K., Bharadwaj K. G., Lymperopoulos A., Ikeda S., Khan R., Hu Y., Agarwal R., Yu S., Jiang H., Steinberg S. F., et al. 2011. Cardiomyocyte lipids impair beta-adrenergic receptor function via PKC activation. Am. J. Physiol. Endocrinol. Metab. 300: E489–E499 - PMC - PubMed
    1. Listenberger L. L., Han X., Lewis S. E., Cases S., Farese R. V., Jr, Ory D. S., Schaffer J. E. 2003. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. USA. 100: 3077–3082 - PMC - PubMed
    1. Cases S., Smith S. J., Zheng Y. W., Myers H. M., Lear S. R., Sande E., Novak S., Collins C., Welch C. B., Lusis A. J., et al. 1998. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc. Natl. Acad. Sci. USA. 95: 13018–13023 - PMC - PubMed
    1. Liu L., Zhang Y., Chen N., Shi X., Tsang B., Yu Y. H. 2007. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J. Clin. Invest. 117: 1679–1689 - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources