title: Lipotoxicity in obesity and diabetes-related cardiac dysfunction.
abstract: Patients with type 2 diabetes (T2D) are at increased risk for cardiovascular diseases including diabetic cardiomyopathy, which is ventricular dysfunction independent of underlying coronary artery disease and/or hypertension. With numerous advancements in our ability to detect ventricular dysfunction, as well as the molecular mechanisms contributing to ventricular dysfunction in diabetic patients, it is now appreciated that diabetic cardiomyopathy is becoming more prevalent in our population. In spite of these advancements, we do not have any specific therapies currently approved for treating this condition. As obesity increases the risk for both T2D and cardiovascular disease, it has been postulated that obesity-mediated alterations in myocardial lipid metabolism are critical to the pathophysiology of diabetic cardiomyopathy. Indeed, animal studies have provided strong evidence that alterations in either myocardial fatty acid uptake or fatty acid β-oxidation lead to the accumulation of various lipid intermediates including triacylglycerol, diacylglycerol, ceramide, long-chain acyl CoA, acylcarnitine, and many others that are tightly linked to the progression of ventricular dysfunction. We review herein why lipid intermediates accumulate in the heart during obesity and/or T2D, with a focus on which of these various lipid intermediates may be responsible for cardiac lipotoxicity, and whether findings in animal models are relevant to humans. An improved understanding of how these lipid intermediates accumulate in the heart and how they produce cardiac toxicity may lead to the discovery of novel targets to pursue for the treatment of human diabetic cardiomyopathy. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Zlobine
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Keshav
authors.initials: K
authors.lastname: Gopal
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada. Electronic address: jussher@ualberta.ca.
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
mesh_terms: D000818:Animals; D058065:Diabetic Cardiomyopathies / Q000473:pathology* / Q000628:therapy; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000633:toxicity*; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000473:pathology* / Q000628:therapy
chemical_list: D005227:Fatty Acids; D008055:Lipids
keywords: Acylcarnitine; Cardiac lipotoxicity; Cardiomyopathy; Ceramide; Diabetes; Diacylglycerol; Fatty acid metabolism; Lipid intermediates; Obesity; Type 2 diabetes