Acid sphingomyelinase plays important roles in
ceramide homeostasis, which has been proposed to be linked to
insulin resistance. To test this association in vivo,
acid sphingomyelinase deletion (asm(-/-)) was transferred to mice lacking the
low density lipoprotein receptor (ldlr(-/-)), and then offsprings were placed on control or modified (enriched in saturated fat and
cholesterol) diets for 10 weeks. The modified diet caused
hypercholesterolemia in all genotypes; however, in contrast to asm(+/+)/ldlr(-/-), the
acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although
sphingomyelin and other
sphingolipids were substantially elevated, and the liver was enlarged. asm(-/-)/ldlr(-/-) mice on a modified diet did not accumulate body fat and were protected against diet-induced
hyperglycemia and
insulin resistance. Experiments with hepatocytes revealed that
acid sphingomyelinase regulates the partitioning of the major
fatty acid in the modified diet,
palmitate, into two competitive and inversely related pools, triacylglycerides and
sphingolipids, apparently via modulation of
serine palmitoyltransferase, a rate-limiting
enzyme in de novo
sphingolipid synthesis. These studies provide evidence that
acid sphingomyelinase activity plays an essential role in the regulation of
glucose metabolism by regulating the hepatic accumulation of triacylglycerides and
sphingolipids during consumption of a diet rich in saturated
fats.