ULK1 prevents cardiac dysfunction in obesity through autophagy-meditated regulation of lipid metabolism
Authors: Jang Won Park
Dong-Ryeol Ryu
Kyung Eun Lee
Minna Woo
Minae An
Ji Ha Choi
Minsuk Kim
Eun-Mi Park
Journal: Cardiovascular Research (2017)
Discipline: CLINICAL MEDICINE
Keywords: Autophagy; Heart; Lipoprotein Lipase; Obesity; ULK1.
Affiliations: Department of Pharmacology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea., Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, Republic of Korea., Department of Orthopedic surgery, School of Medicine, Ewha Womans University, Seoul, Republic of Korea., Department of Medicine, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.

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/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. 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. 

Retracted: No

PubPeer comments:
 The strange shape of the WB lines and complete lack of the background. Could authors provide originals of the WB? Fig1G ![file] ![file] Fig3A ![file] ![file] Fig4C ![file] ![file] , 
 We submitted the original data to the Cardiovascular Research on this issue, and the journal confirmed that there were no problems. ,