Taxonomy: 2013

OBJECTIVES:

Anthracyclines such as doxorubicin are an effective class of antineoplastic agents. Despite its efficacy in the treatment of a variety of cancers, the clinical use of doxorubicin is limited by cardiac side effects. While it has been suggested that doxorubicin alters myocardial fatty acid metabolism, it is poorly understood whether this is the case and whether variations in myocardial triacylglycerol (TAG) metabolism contribute to doxorubicin induced cardiotoxicity. Since TAG catabolism in the heart is controlled by adipose triglyceride lipase(ATGL), this study examined the influence of doxorubicin on cardiac energy metabolism and TAG values as well as the consequence of forced expression of ATGL in the setting of doxorubicin induced cardiotoxicity.

DESIGN AND SETTING:

Wild type (WT) mice and mice with cardiomyocyte specific ATGL overexpression were divided into two groups per genotype that received a weekly intraperitoneal injection of saline or doxorubicin for 4 weeks.

RESULTS:

Four weeks of doxorubicin administration significantly impaired in vivo systolic function (11% reduction in ejection fraction, p<0.05), which was associated with increased lung wet to dry weight ratios. Furthermore, doxorubicin induced cardiac dysfunction was independent of changes in glucose and fatty acid oxidation in WT hearts. However, doxorubicin administration significantly reduced myocardial TAG content in WT mice (p<0.05). Importantly, cardiomyocyte specific ATGL overexpression and the resulting decrease in cardiacTAG accumulation attenuated the decrease in ejection fraction (p<0.05) and thus protected mice from doxorubicin induced cardiacdysfunction.

CONCLUSIONS:

Taken together, our data suggest that chronic reduction in myocardial TAG content by cardiomyocyte specific ATGL overexpression is able to prevent doxorubicin induced cardiac dysfunction.

https://heart.bmj.com/content/99/14/1041.long

Although diabetic cardiomyopathy is associated with enhanced intramyocardial triacylglycerol (TAG) levels, the role of TAG catabolizing enzymes in this process is unclear. Because the TAG hydrolase, adipose triglyceride lipase (ATGL), regulates baseline cardiac metabolism and function, we examined whether alterations in cardiomyocyte ATGL impact cardiac function during uncontrolled type 1 diabetes. In genetic (Akita) and pharmacological (streptozotocin) murine models of type 1 diabetes, cardiac ATGL protein expression and TAG content were significantly increased. To determine whether increased ATGL expression during diabetes is detrimental or beneficial to cardiac function, we studied streptozotocin-diabetic mice with heterozygous ATGL deficiency and cardiomyocyte-specific ATGL overexpression. After diabetes, streptozotocin-diabetic mice with heterozygous ATGL deficiency displayed increased TAG accumulation, lipotoxicity, and diastolic dysfunction comparable to wild-type mice. In contrast, myosin heavy chain promoter (MHC)-ATGL mice were resistant to diabetes-induced increases in intramyocardial TAG levels, lipotoxicity, and cardiac dysfunction. Moreover, hearts from diabetic MHC-ATGL mice exhibited decreased reliance on palmitate oxidation and blunted peroxisome proliferator–activated receptor-α activation. Collectively, this study shows that after diabetes, increased cardiac ATGL expression is an adaptive, albeit insufficient, response to compensate for the accumulation of myocardialTAG, and that overexpression of ATGL is sufficient to ameliorate diabetes-induced cardiomyopathy.

Read online – http://diabetes.diabetesjournals.org/content/62/5/1464.long

Myocardial triacylglycerol (TAG) constitutes a highly dynamic fatty acid (FA) storage pool that can be used for an energy reserve in the cardiomyocyte. However, derangements in myocardial TAG metabolism and accumulation are commonly associated with cardiac disease, suggesting an important role of intramyocardial TAG turnover in the regulation of cardiac function. In cardiomyocytes, TAG is synthesized by acyltransferases and phosphatases at the sarcoplasmic reticulum and mitochondrial membrane and then packaged into cytosolic lipid droplets for temporary storage or into lipoproteins for secretion. A complex interplay among lipases, lipase regulatory proteins, and lipid droplet scaffold proteins leads to the controlled release of FAs from the cardiac TAG pool for subsequent mitochondrial β-oxidation and energy production. With the identification and characterization of proteins involved in myocardial TAG metabolism as well as the identification of the importance of cardiac TAG turnover, it is now evident that adequate regulation of myocardial TAG metabolism is critical for both cardiac energy metabolism and function. In this article, we review the current understanding of myocardial TAG metabolism and discuss the potential role of myocardial TAG turnover in cardiac health and disease.

This article is part of a Special Issue entitled “Focus on Cardiac Metabolism”.

Read online – https://www.jmmc-online.com/article/S0022-2828(12)00244-1/fulltext?code=yjmcc-site

Read online – https://academic.oup.com/cardiovascres/article/99/3/442/296783