thermozymocidin and Heart-Failure

Obesity is a major health concern that increases the risk for insulin resistance, type 2 diabetes (T2D), and cardiovascular disease. Thus, an enormous research effort has been invested into understanding how obesity-associated dyslipidemia and obesity-induced alterations in lipid metabolism increase the risk for these diseases. Accordingly, it has been proposed that the accumulation of lipid metabolites in organs such as the liver, skeletal muscle, and heart is critical to these obesity-induced pathologies. Ceramide is one such lipid metabolite that accumulates in tissues in response to obesity, and both pharmacological and genetic strategies that reduce tissue ceramide levels yield salutary actions on overall metabolic health. We will review herein why ceramide accumulates in tissues during obesity and how an increase in intracellular ceramide impacts cellular signaling and function as well as potential mechanisms by which reducing intracellular ceramide levels improves insulin resistance, T2D, atherosclerosis, and heart failure. Because a reduction in skeletal muscle ceramide levels is frequently associated with improvements in insulin sensitivity in humans, the beneficial findings reported for reducing ceramides in preclinical studies may have clinical application in humans. Therefore, modulating ceramide metabolism may be a novel, exciting target for preventing and/or treating obesity-related diseases.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Ceramides; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Acids, Monounsaturated; Heart Failure; Humans; Insulin Resistance; Lipid Metabolism; Liver; Mitochondria; Molecular Targeted Therapy; Muscle, Skeletal; Myocardium; Obesity

Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL(GPI)). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL(GPI) hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.

Topics: Animals; Biomarkers; Cardiomyopathy, Dilated; Cardiotoxins; Cattle; Ceramides; Fatty Acids; Fatty Acids, Monounsaturated; Gene Deletion; Gene Expression Regulation; Glucose; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Glycosylphosphatidylinositols; Heart; Heart Failure; Humans; Lipoprotein Lipase; Mice; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Phosphorylation; Serine C-Palmitoyltransferase; Survival Rate