Acidic sphingomyelinase controls diet-induced insulin sensitivity, adipose tissue homeostasis and hepatic steatosis

Abstract

Sphingolipids, in particular ceramide, can blunt the insulin signaling to insulin, which may be of relevance in the perturbation of metabolic homeostasis. Ceramide can arise by different pathways, including the de novo synthesis in the endoplasmic reticulum or sphingomyelin hydrolysis by sphingomyelinases (SMases). Although recent findings indicated a role for acidic SMase (ASMase) in insulin signaling and hepatic steatosis in a LDL receptor deficient genetic background (Deevska et al, J. Biol. Chem. 2009), the function of ASMase per se in diet-induced insulin sensitivity, hepatic steatosis and liver damage has not been previously examined. Thus, our aim was to examine these parameters in ASMase deficient mice. [Methods]: A 60% KCal diet derived from fat (HFD) was administered for 12 weeks to ASMase+/+, ASMase+/− and ASMase−/− mice. Blood glucose was monitored every 4 weeks and glucose and insulin tolerance tests were performed at week 10 and 14. Mice were sacrificed at 16 weeks of age, analyzing blood and tissue lipid profiles, hepatic steatosis, ceramide lipidomics by HPLC/MS analysis and liver damage. [Results]: ASMase+/− mice exhibiting a 40% residual ASMase activity showed a similar phenotype to ASMase+/+ following HFD feeding. Yet ASMase−/− mice showed higher body weight, higher blood glucose levels and less glucose tolerance upon HFD feeding. While ASMase+/+ or ASMase+/− mice accumulated fat in the adipose tissue after HFD feeding, ASMase−/− mice were blind to this dietary effect, although they increased their liver weight. Lipid analysis showed increased total liver sphingomyelin and cholesterol but decreased liver triglyceride content in ASMase−/− mice compared to ASMase+/+ mice. Lipidomic analyses indicated similar ceramide species in wild type and ASMase−/− fed HFD, although some long chain ceramides were altered in ASMase KO mice. Moreover, wild type mice exhibited diet-induced liver damage (H&E and ALT/AST release); however, although the ASMase−/− fenotype included a mild initial liver damage, mice were protected against HFD-induced enhanced liver injury. [Conclusions]: ASMase regulates fat accumulation in adipose tissue, body weight gain and glucose tolerance following HFD. ASMase is required for diet induced macrovesicular steatosis and its deficiency ameliorates HFD-mediated liver damage.