Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

Nonalcoholic fatty liver disease is the most common liver disease in industrialized nations and is strongly associated with hepatic insulin resistance, a key driver of type 2 diabetes. Although stored hepatic triglyceride is not thought to directly impair insulin action, two lipid classes proposed to mediate lipid-induced hepatic insulin resistance are ceramides and diacylglycerols (DAGs). A causal role for DAGs in hepatic insulin resistance is supported by human correlative studies and a direct pathophysiologic mechanism in rodents but challenged by a few rodent models with increased hepatic DAG but preserved hepatic insulin sensitivity. A causal role for ceramides in hepatic insulin resistance is supported by several rodent models in which decreasing ceramides improves hepatic insulin action but challenged by an inconsistent relationship between hepatic ceramide content and hepatic insulin resistance. Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance. Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance. a large class of lipids, many of which derive from the condensation of serine and palmitoyl CoA by serine palmitoyltransferase (SPT). Many ceramide species are bioactive and participate in diverse cellular signaling pathways. a class of lipids comprising a three-carbon glycerol backbone, two carbons of which are linked to fatty acyl chains of varying length. DAG exists in three stereoisomers (sn-1,2, sn-1,3, and sn-2,3); only sn-1,2-DAG is capable of activating PKC isoforms. DAG is generated through several metabolic fluxes, including triglyceride hydrolysis, triglyceride synthesis, and phosphoinositide hydrolysis. a condition in which the cellular response to a given ambient insulin concentration is decreased relative to a normal control. Insulin resistance as generally understood incorporates both decreased insulin sensitivity (a right shift in the insulin dose–response curve) and decreased insulin responsiveness (an impaired maximal response to high insulin concentrations). Insulin resistance has diverse manifestations in different tissues and is a component of the ‘metabolic syndrome’ that predicts incident T2D. increased liver triglyceride content without an alternative etiology (e.g., alcohol use, starvation, medications). NAFLD is a risk factor for nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma. NAFLD may or may not be accompanied by biochemical signs of hepatocellular injury, such as elevated serum transaminase activity, and is clinically silent in many patients.