Increasing Fatty Acid Oxidation Prevents High-Fat Diet–Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy
- 29 June 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 142 (10), 983-997
- https://doi.org/10.1161/circulationaha.119.043319
Abstract
Background: Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acids transport into mitochondria via deletion of acetyl-CoA carboxylase 2 (ACC2) does not cause cardiomyopathy in non-obese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity induced cardiomyopathy, and if so, to elucidate the underlying mechanisms. Methods: We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen inducible model (ACC2 iKO). Control (Con) and ACC2 iKO mice were subjected to high fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function and mitophagy activity were examined. Results: Despite both Con and ACC2 iKO mice exhibiting similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD induced cardiac dysfunction, pathological remodeling as well as mitochondria dysfunction. Similarly, increasing FAO by knock down of ACC2 prevented palmitate induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was partially attenuated in ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD induced downregulation of parkin. During stimulation for mitophagy, mitochondria localized parkin was severely reduced in Con HFD-fed mouse heart, which was partially restored in ACC2 iKO HFD-fed mice. Conclusions: These data show that increasing cardiac FAO alone does not cause cardiac dysfunction but protect against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD induced obesity is mediated, in part, by maintenance of mitochondria function through regulating parkin mediated mitophagy. Our findings also suggest that targeting the parkin dependent mitophagy pathway could be an effective strategy against the development of obesity induced cardiomyopathy.This publication has 56 references indexed in Scilit:
- Lipid Metabolism and Toxicity in the HeartCell Metabolism, 2012
- Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in miceJCI Insight, 2012
- PINK1- and Parkin-mediated mitophagy at a glanceJournal of Cell Science, 2012
- A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heartBasic Research in Cardiology, 2011
- Mitochondria in the diabetic heartCardiovascular Research, 2010
- Lipotoxicity in the heartBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2010
- DGAT1 Expression Increases Heart Triglyceride Content but Ameliorates LipotoxicityOnline Journal of Public Health Informatics, 2009
- Increased Glucose Uptake and Oxidation in Mouse Hearts Prevent High Fatty Acid Oxidation but Cause Cardiac Dysfunction in Diet-Induced ObesityCirculation, 2009
- A short duration of high-fat diet induces insulin resistance and predisposes to adverse left ventricular remodeling after pressure overloadAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008
- Parkin is recruited selectively to impaired mitochondria and promotes their autophagyThe Journal of cell biology, 2008