Ceramide dependent lipotoxicity in metabolic diseases

Sphingolipids, a major class of lipids in cell membranes, play diverse roles in biology. They are synthesized by a highly conserved biosynthetic pathway that leads to the production of ceramides, the major precursors of most complex sphingolipids. Almost all known stress stimuli including inflammatory agonists, chemotherapeutics, and saturated fatty acids induce the synthesis of ceramide and its metabolites. A panoply of recent studies has implicated ceramides in the development of the metabolic comorbidities of obesity such as diabetes and cardiovascular diseases. In particular, inhibition of ceramide biosynthesis in rodents ameliorates insulin resistance, diabetes, cardiomyopathy, atherosclerosis, and steatohepatitis. These data implicate ceramides as major contributors to the development of metabolic diseases. This review summarizes recent findings on this emerging class of bioactive lipids with an emphasis on studies using in vivo models to understand their role in metabolic disease.