Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice.
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.
Deevska
Gergana M
GM
Departments of Physiology, Pediatrics, and Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Rozenova
Krassimira A
KA
Giltiay
Natalia V
NV
Chambers
Melissa A
MA
White
James
J
Boyanovsky
Boris B
BB
Wei
Jia
J
Daugherty
Alan
A
Smart
Eric J
EJ
Reid
Michael B
MB
Merrill
Alfred H
AH
Nikolova-Karakashian
Mariana
M
D000818:Animals; D005526:Food, Formulated / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology*; D006943:Hyperglycemia / Q000139:chemically induced / Q000201:enzymology*; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010168:Palmitates / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency* / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*
D010168:Palmitates; D011973:Receptors, LDL; D013107:Sphingolipids; D014280:Triglycerides; D051102:Serine C-Palmitoyltransferase; D013108:Sphingomyelin Phosphodiesterase; D005947:Glucose