Increasing fatty acid oxidation prevents high fat diet induced cardiomyopathy through regulating mitophagy activity

Abstract

Under obese condition, an imbalance between fatty acid uptake and fatty acid oxidation (FAO) promotes the development of cardiac lipotoxicity. We have previously demonstrated that enhancing FAO via Acetyl-CoA carboxylase 2 (ACC2) deletion prevents high fat diet (HFD) induced cardiac dysfunction and attenuates pathological remodeling in obese mice. In this study, we examined the effect of enhancing FAO in regulating mitochondrial function in obese mouse heart. ACC2 flox/flox (Con) and ACC2 flox/flox-MerCreMer+ (iKO) were injected with tamoxifen and subjected to HFD feeding for 24 weeks. Mitochondria oxygen consumption rate in Con HFD-fed hearts were reduced, which was maintained in iKO mice. Electron microscopy analysis revealed that ACC2 iKO mice prevented HFD induced accumulation of damaged mitochondria (3 ± 0.24% (CON) vs. 1.27 ± 0.36% (iKO), p < .05, n = 5). In vitro, palmitate (PA) induced mitochondria fragmation and increased reactive oxggen species production was partially attenuated in cardiomyocytes when ACC2 was knocked down. Knocking down of ACC2 also prevented PA induced cell death (65.2 ± 3.1% vs. 85.3 ± 3.9%, p < .05, n = 3). These data suggest that enhancing FAO prevents HFD induced mitochondria dysfunction. Moreover, HFD treatment reduced the expression of LC3 II and p62 in mitochondria fraction. EM analysis revealed that the number of mitochondria in autophagosome was less in Con HFD-fed heart compared with Con chow-fed group in response to starvation and CCCP treatment. Mt-Keima signal, indicative of mitophagy activity in vivo, decreased in mice with HFD feeding, suggesting that HFD treatment impairs mitophagy activity. However, ACC2 iKO mice partially restored mitophagy in response to HFD feeding. Therefore, the beneficial effect for enhancing FAO in HFD induced obesity model mediates by maintenance of mitochondria function through regulating mitophagy. Our findings suggest that promoting FAO is an effective strategy to resist the development of cardiac lipotoxicity during diet-induced obesity.