Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation.

Abstract

AIMS:

While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as adipose triglyceride lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor α (PPARα) activity and subsequent fatty acid oxidation (FAO). However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARα activity, cardiac function, and metabolism is not known.

METHODS AND RESULTS:

To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (icAtglKO). Within 4-6 weeks following ATGL ablation, icAtglKO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in icAtglKO mice. Analysis of energy metabolism in ex vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression.

CONCLUSIONS:

This study shows that acquired cardiomyocyte-specific ATGL deficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARα signalling.

• Authors: Petra C Kienesberger, Thomas Pulinilkunnil, Jeevan Nagendran, Martin E Young, Juliane G Bogner-Strauss, Hubert Hackl, Rammy Khadour, Emma Heydari, Guenter Haemmerle, Rudolf Zechner, Erin E Kershaw, Jason R B Dyck
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 99 Issue 3 Pg. 442-51 (Aug 01 2013) ISSN: 1755-3245 [Electronic] England
• PMID: 23708736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• PPAR alpha
• Lipase
• PNPLA2 protein, mouse

Topics

• Animals
• Cardiomyopathies (metabolism, pathology, physiopathology)
• Disease Models, Animal
• Fatty Acids (metabolism)
• Lipase (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria, Heart (metabolism)
• Myocytes, Cardiac (metabolism)
• Oxidation-Reduction
• PPAR alpha (metabolism)
• Signal Transduction