Differential Regulation of Dihydroceramide Desaturase by Palmitate versus Monounsaturated Fatty Acids

Abstract

Much data implicate saturated fatty acids in deleterious processes associated with obesity, diabetes, and the metabolic syndrome. Many of these changes may be due to aberrant generation of bioactive lipids when saturated fatty acid availability to tissues is increased. On the other hand, studies are emerging that implicate the monounsaturated fatty acid oleate in protection from saturated fat mediated toxicity; however, the mechanisms are not well understood. Our data demonstrate a novel role for palmitate in increasing mRNA encoding DES1, which is the enzyme responsible for generating ceramide from its precursor dihydroceramide and thus controls synthesis of the bioactive lipid ceramide. Moreover, co-treatment with oleate prevented the increase in ceramide, and this occurred through attenuation of the increase in message and activity of DES1. Knockdown of DES1 also protected from palmitate-induced insulin resistance, and overexpression of this enzyme ameliorated the protective effect of oleate. Together, these findings provide insight into the mechanisms of oleate-mediated protection against metabolic disease and provide novel evidence for fatty acid-mediated regulation of a key enzyme of ceramide biosynthesis.The rise in obesity in recent years has initiated a pandemic of metabolic disease including heart disease and diabetes (1, 2). Perturbations in lipid metabolism and/or endocrine function that occur in obesity likely mediate the development of a disorders, including insulin resistance, nonalcoholic fatty liver disease, pancreatic cell death, hypertension, and the "metabolic syndrome" (3, 4). Although the mechanistic links between obesity and these pathophysiological processes remain incompletely understood, one proposed mechanism is that the elevation in plasma lipids associated with obesity overloads tissues with precursors for synthesis of bioactive lipids, including diacylglycerols (DAG) 2 and ceramides (5, 6).Epidemiological data link diets high in saturated fatty acids with increased incidence of metabolic disease (6, 7). Supporting a mechanistic connection between saturated fatty acids and metabolic syndrome, many studies demonstrate that the saturated fatty acid palmitate promotes insulin resistance in heart, adipose, and skeletal muscle (8 -10). On the other hand, data are emerging which support that unsaturated fatty acids such as oleate have protective effects against palmitate toxicity, though the mechanisms are not fully understood (11,12).Several studies demonstrate that ceramide plays a key role in insulin resistance in human skeletal muscle cells (13-15). Biosynthesis of sphingolipids including ceramide begins with condensation of serine with acyl-CoA such as palmitoyl-CoA. Exposing muscle cells to palmitate increased ceramide synthesis and inhibited insulin stimulation of Akt/protein kinase B, a serine/threonine kinase that is a central mediator of insulinstimulated anabolic metabolism (13); moreover, inhibiting ceramide synthesis negated the antagonistic effect of saturated free fatty acid...

Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

“…Notably, the monounsaturated fatty acid oleate completely reversed palmitate-induced autophagosome accumulation. Previous studies showed that oleate exerts different cellular effects than palmitate ( 43 ). It prevents lipototoxic effects of palmitate presumably by channelling toxic lipid intermediates of palmitate metabolism to the relatively benign triacylglycerol depot, which we also observed in H9C2 CMs, and may explain its effect on the reversal of palmitateinduced autophagy ( 44 ).…”

Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes

“…In contrast, wild-type mice fed standard lard-based high-fat diets (LBD) failed to develop a DbCM-like phenotype until very late time points, if at all, and insulin resistance and other aspects of the diabetic phenotype were less pronounced in this model system than in transgenic animals (4)(5)(6)(7)(8)(9). This may result from the high levels of protective unsaturated fatty acids (UFAs) contained in these diets (10)(11)(12). Thus, while these transgenic model systems produce a robust DbCM phenotype, they are unable to reveal clinically relevant roles of specific lipid species in the molecular pathogenesis of DbCM.…”

“…Further complicating this effort, previously investigated dietinduced obesity models, which utilize high-fat feeding in wildtype mice, poorly reproduced the cardiac parameters of DbCM, including hypertrophy. This may be because the fatty acid profile of lard, which is the fat source for these diets, contains close to 60% combined oleic and linoleic acids, which have been shown to protect against lipotoxicity and might be expected to attenuate lipotoxic outcomes (11,72).…”

Ablation of Dihydroceramide Desaturase 1, a Therapeutic Target for the Treatment of Metabolic Diseases, Simultaneously Stimulates Anabolic and Catabolic Signaling

“…Indeed, knockdown of Des1 in cultured myotubes prevented the antagonistic effects of saturated fatty acids on insulin signaling (20,45), and muscles from mice haploinsufficient for Des1 were protected from lipid-and glucocorticoid-induced insulin resistance (16). Moreover, palmitate was shown to induce the enzyme in vitro (20,45), and high-fat feeding did so in vivo (20). Lastly, fenretinide inhibited the enzyme in vivo in both wild-type and high-fat-fed mice, as detected by alterations in ceramide/dihydroceramide ratios, and this accounted at least partially for the drug insulin sensitizing effects (20).…”