Cardiac specific PPAR alpha knock-down protects against cardiac lipid accumulation during metabolic stress

Abstract

A dysregulated lipid metabolism contributes to the pathological development of a wide array of diseases including Type 2 Diabetes and associated cardiovascular diseases. One main regulator of cardiac lipid metabolism is the transcription factor Peroxisome Proliferator Activated Receptor α (PPARα). PPARα has been shown to have regulatory effects on many proteins that are integral for the proper regulation of lipid metabolism including those involved in fatty acid oxidation, mitochondria, and lipid droplets. After triglycerides (TG) accumulate and are stored in lipid droplets, the fat is then transferred from lipid droplets to mitochondria where the fatty acids undergo fatty acid oxidation and are used for ATP synthesis. In this research we aimed to determine how cardiac PPARα regulates lipid metabolism and the organelles responsible for its homeostasis in the heart during metabolic stress in the context of obesity. To study this, we used our tamoxifen-inducible cardiomyocyte specific PPARα knockout (cPPARα -/- ) mouse. To induce obesity, we fed Control and cPPARα -/- mice a high fat diet (HFD) for 5 weeks. Our results show that the TG content is lower in hearts from cPPARα -/- vs Control mice fed the HFD. cPPARα -/- vs Control hearts also had a lower expression of Plin2 (a key lipid droplet protein) when fed a HFD. also agrees with our previous findings in fasted/fed hearts. Interestingly, this agrees with our previous findings that the hearts in cPPARα -/- mice were protected against the elevation in TG that normally occurs in response to short term fasting (16 hr fast). Therefore, a reduction in cardiac PPARα protects against lipid accumulation in the heart. As mitochondrial dysfunction has been linked to the cardiac dysfunction present in diabetic hearts and may be involved in regulating lipid accumulation, we next wanted to test whether cPPARα -/- affected mitochondrial function. Measurements of mitochondrial stress proteins have not suggested any elevation in mitochondrial dysfunction in the cPPARα -/- hearts either at baseline or in response to the HFD or 16 hr fast. Interestingly, cPPARα -/- hearts had a higher expression of the uncut ATF6 protein than the control hearts when fasted which suggests that the cPPARα -/- hearts may have less mitochondrial stress due to less excess ROS in the heart. In agreement with this, echocardiography measurements have so far not indicated any reduction in the cardiac function of cPPARα -/- vs control mice. In the future it will be important to look into mitochondrial dysfunction in greater depth including the regulation of mitochondrial fission and fusion pathways. Overall, this suggests that cardiac PPARα may protect against cardiac lipid accumulation in obesity and that this may be through the regulation of Plin2 and mitochondrial stress pathways. ND EPSCoR This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.