TY - JOUR
T1 - Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia in mice
AU - Deevska, Gergana M.
AU - Rozenova, Krassimira A.
AU - Giltiay, Natalia V.
AU - Chambers, Melissa A.
AU - White, James
AU - Boyanovsky, Boris B.
AU - Wei, Jia
AU - Daugherty, Alan
AU - Smart, Eric J.
AU - Reid, Michael B.
AU - Merrill, Alfred H.
AU - Nikolova-Karakashian, Mariana
PY - 2009/3/27
Y1 - 2009/3/27
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M807800200
DO - 10.1074/jbc.M807800200
M3 - Article
C2 - 19074137
AN - SCOPUS:67649763475
SN - 0021-9258
VL - 284
SP - 8359
EP - 8368
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 13
ER -