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ULK1 prevents cardiac dysfunction in obesity through autophagy-meditated regulation of lipid metabolism

Title
ULK1 prevents cardiac dysfunction in obesity through autophagy-meditated regulation of lipid metabolism
Authors
An M.Ryu D.-R.Won Park J.Ha Choi J.Park E.-M.Eun Lee K.Woo M.Kim M.
Ewha Authors
이경은박은미류동열박장원김민석
SCOPUS Author ID
이경은scopus; 박은미scopus; 류동열scopus; 박장원scopus; 김민석scopus
Issue Date
2017
Journal Title
Cardiovascular Research
ISSN
0008-6363JCR Link
Citation
vol. 113, no. 10, pp. 1137 - 1147
Keywords
AutophagyHeartLipoprotein LipaseObesityULK1
Publisher
Oxford University Press
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. 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/ulk1 fl/fl), Lpl (Myh6-cre/Lpl fl/fl), and mice with a combined deficiency (Myh6-cre/ulk1 fl/fl Lpl fl/fl). Similar to genetic and dietary models of obesity, Myh6-cre/ulk1 fl/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/ulk1 fl/fl Lpl fl/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. 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. © The Author 2017.
DOI
10.1093/cvr/cvx064
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의과대학 > 의학과 > Journal papers
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