Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

Liu, Li; Trent, Chad M.; Fang, Xiang; Son, Ni-Huiping; Jiang, Hongfeng; Blaner, William S.; Hu, Yixin; Yin, Yuxin; Farese, Robert V.; Homma, Shunichi; Turnbull, Andrew V.; Eriksson, Jan W.; Hu, Shilian; Ginsberg, Henry N.; Huang, Li‐Shin; Goldberg, Ira J.

doi:10.1074/jbc.m114.601864

Cited by 61 publications

(51 citation statements)

References 51 publications

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“…For example, murine fibroblasts lacking DGAT1 are sensitive to oleate-induced cell death (Listenberger et al, 2003). Additionally, several tissue-specific transgenic models of DGAT1 overexpression have reported beneficial effects that are consistent with a role of DGAT1-mediated ER protection (Chen et al, 2002b; Koliwad et al, 2010; Liu et al, 2009), and deletion of DGAT1 in heart increased lipotoxicity in a murine model (Liu et al, 2014). We now show a mechanism for this protection: the detoxification of lipid species by DGAT1 prevents buildup of toxic lipids in the ER that can lead to sustained UPR activation.…”

Section: Discussionmentioning

confidence: 55%

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

et al. 2017

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SUMMARY Triglyceride (TG) storage in adipose tissue provides the major reservoir for metabolic energy in mammals. During lipolysis, fatty acids (FAs) are hydrolyzed from adipocyte TG stores and transported to other tissues for fuel. For unclear reasons, a large portion of hydrolyzed FAs in adipocytes is re-esterified to TGs in a “futile”, ATP-consuming, energy dissipating cycle. Here we show that FA re-esterification during adipocyte lipolysis is mediated by DGAT1, an ER-localized DGAT enzyme. Surprisingly, this re-esterification cycle does not preserve TG mass, but instead functions to protect the ER from lipotoxic stress and related consequences, such as adipose tissue inflammation. Our data reveal an important role for DGAT activity and TG synthesis generally in averting ER stress and lipotoxicity, with specifically DGAT1 performing this function during stimulated lipolysis in adipocytes.

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Section: Discussionmentioning

confidence: 55%

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

et al. 2017

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“…Elevated cardiac ceramide levels have also been observed in a variety of obesity models, including genetic models of ectopic lipid accumulation such as db/db and ob/ob , diacylglycerol acyl-transferase ( DGAT )- or adipose triglyceride lipase ( ATGL )-deficient mice (Demarco et al, 2013; Dobrzyn et al, 2015; Gao et al, 2015; Liu et al, 2014), and mice overexpressing peroxi-some proliferator-activated receptor α/γ(PPARα/γ ) or fatty acid transport protein 1 (FATP1) (Baranowski et al, 2007; Chui et al, 2005; Finck et al, 2003). However, the potential role of ceramide in the pathophysiology of LCM is poorly understood, in part because of the complexity of mammalian metabolism.…”

Section: Introductionmentioning

confidence: 99%

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

et al. 2018

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SUMMARY Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals.

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“…These lipids could be involved in the heart failure phenotype of Tg-FASN mice because they trigger a wide spectrum of cardiotoxic mechanisms, which involves, for example, the excessive formation of reactive oxygen species, an increased endoplasmic reticulum stress, enhanced apoptosis, and mitochondrial dysfunction (22,26). Additionally, increased cardiac contents of DAG and ceramide could mediate the activation of protein kinase C (PKC), which further decreases heart function (22,27,28). Thus, FASN transgenic hearts developed signs of heart failure with cardiotoxic lipid load in addition to the dysfunctional energy substrate metabolism, which was detected in isolated cardiomyocytes.…”

Section: Fasn Transgenic Cardiomyocytes Developed a Dysfunctionalmentioning

confidence: 99%

“…Cellular cAMP, total cardiac free fatty acids (FFA), and triacylglycerol (TAG) contents were analyzed as detailed previously (11,21). Cardiac contents of diacylglycerol (DAG) and ceramides were determined with the DAG kinase assay method as described (22).…”

Section: Generation Of Transgenic Mice and Animal Experiments-mentioning

confidence: 99%

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Alla

Graemer

et al. 2016

Journal of Biological Chemistry

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Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor ␥). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.Heart failure is a debilitating syndrome that involves insufficient cardiac performance. Multiple pathomechanisms have been elucidated, but treatment options remain insufficient, and hence the mortality of heart failure is high (1). The causes of heart failure are complex with ischemic heart disease being the most frequently associated condition (2). Co-existing disorders such as diabetes, hypertension, and obesity further deteriorate symptoms (3). Despite having a different etiology, late-stage heart failure is commonly characterized by severe changes in myocardial substrate metabolism, with a switch from fatty acid oxidation toward predominant glycolysis (4 -6). Conflicting evidence exists as to whether this substrate switch is beneficial or detrimental (7), but several previous studies have indicated that an increased availability of lipid substrates that counteract the substrate switch could improve cardiac function (7,8). Moreover, treatment options, which improve substrate availability, are attractive because the failing heart is often considered to be "an engine running out of fuel" (9).Following this concept, we aimed to investigate the impact of improved cardiac substrate availability by generating transgenic mice with myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. Such an approach is also supported by data obtained for myocardium-specific Fasn deficiency, which have revealed the cardioprotective potential of Fasn (10). Moreover, hearts from patients with heart failure showed an increased express...

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Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

Cited by 61 publications

References 51 publications

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

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