Back to Search
Start Over
ULK1 prevents cardiac dysfunction in obesity through autophagy-meditated regulation of lipid metabolism.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2017 Aug 01; Vol. 113 (10), pp. 1137-1147. - Publication Year :
- 2017
-
Abstract
- Aims: Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis.<br />Methods and Results: In both genetic and dietary models of obesity, we observed a substantial increase in cardiac LPL protein levels without any change in messenger ribonucleic acid (mRNA). This was accompanied by a dramatic down-regulation of autophagy in the heart, as revealed by reduced levels of unc-51 like kinase-1 (ULK1) protein. To further explore the relationship between cardiac LPL and autophagy, we generated cardiomyocyte-specific knockout mice for ulk1 (Myh6-cre/ulk1fl/fl), Lpl (Myh6-cre/Lplfl/fl), and mice with a combined deficiency (Myh6-cre/ulk1fl/flLplfl/fl). Similar to genetic and dietary models of obesity, Myh6-cre/ulk1fl/fl mice had a substantial increase in cardiac LPL levels. When these mice were fed a high-fat diet (HFD), they showed elevated cardiac TG levels and deterioration in heart function. However, with combined deletion of LPL and ULK1 in Myh6-cre/ulk1fl/flLplfl/fl mice, HFD feeding did not lead to alterations in levels of TG or diacylglycerol, or in cardiac function. To further elucidate the role of autophagy in cardiac lipid metabolism, we infused a peptide that enhanced autophagy (D-Tat-beclin1). This effectively lowered LPL levels at the coronary lumen by restoring autophagy in the genetic model of obesity. This decrease in cardiac luminal LPL was associated with a reduction in TG levels and recovery of cardiac function.<br />Conclusion: These results provide clear evidence of the critical role of modulating cardiac LPL activity through autophagy-mediated proteolytic clearance as a potential novel strategy to overcome obesity-related cardiomyopathy.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Autophagy-Related Protein-1 Homolog deficiency
Autophagy-Related Protein-1 Homolog genetics
Beclin-1 metabolism
Cells, Cultured
Diet, High-Fat
Disease Models, Animal
Enzyme Stability
Genetic Predisposition to Disease
Heart Diseases enzymology
Heart Diseases pathology
Heart Diseases physiopathology
Hydrolysis
Isolated Heart Preparation
Lipolysis
Lipoprotein Lipase genetics
Lipoprotein Lipase metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Cardiac pathology
Myosin Heavy Chains genetics
Myosin Heavy Chains metabolism
Obesity enzymology
Obesity pathology
Obesity physiopathology
Phenotype
Proteolysis
Signal Transduction
Time Factors
Autophagy
Autophagy-Related Protein-1 Homolog metabolism
Fatty Acids metabolism
Heart Diseases prevention & control
Myocardial Contraction
Myocytes, Cardiac enzymology
Obesity complications
Triglycerides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 113
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 28430962
- Full Text :
- https://doi.org/10.1093/cvr/cvx064