Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP‐activated protein kinase suppression

Abstract

Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). Because sphingolipids regulate AKT activation, we investigated the role of ASM in hepatic glucose and lipid metabolism. Initially, we overexpressed ASM in the livers of wild-type and diabetic db/db mice by adenovirus vector (Ad5ASM). In these mice, glucose tolerance was improved, and glycogen and lipid accumulation in the liver were increased. Using primary cultured hepatocytes, we confirmed that ASM increased glucose uptake, glycogen deposition, and lipid accumulation through activation of AKT and glycogen synthase kinase-3β. In addition, ASM induced up-regulation of glucose transporter 2 accompanied by suppression of AMP-activated protein kinase (AMPK) phosphorylation. Loss of sphingosine kinase-1 (SphK1) diminished ASM-mediated AKT phosphorylation, but exogenous S1P induced AKT activation in hepatocytes. In contrast, SphK1 deficiency did not affect AMPK activation. These results suggest that the SphK/S1P pathway is required for ASM-mediated AKT activation but not for AMPK inactivation. Finally, we found that treatment with high-dose glucose increased glycogen deposition and lipid accumulation in wild-type hepatocytes but not in ASM−/− cells. This result is consistent with glucose intolerance in ASM−/− mice. In conclusion, ASM modulates AKT activation and AMPK inactivation, thus regulating glucose and lipid metabolism in the liver.—Osawa, Y., Seki, E., Kodama, Y., Suetsugu, A., Miura, K., Adachi, M., Ito, H., Shiratori, Y., Banno, Y., Olefsky, J. M., Nagaki, M., Moriwaki, H., Brenner, D. A., Seishima, M. Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.

Liver acid sphingomyelinase inhibits growth of metastatic colon cancer

“…AdASM-derived GFP was expressed in the hepatocytes, but not in the tumor cells (Supplemental Figure 2B). In support of the results of our previous study (27), AdASM increased ASM activity in the liver (Supplemental Figure 2C). In addition, ASM-chimeric mice,…”

“…Moreover, host ASM deficiency increased, while overexpression of ASM in the liver decreased, the growth of liver tumors after inoculation with colon cancer cells, which suggests that ASM in host cells contributes to antitumor defense. Among the roles that ASM plays in liver cells, ASM in hepatocytes stimulates glucose uptake, resulting in improvement of glucose tolerance in mice through S1P production (27). ASM has pleiotropic signaling functions related to posttranslational processing of ASM, and secretory and lysosomal ASM (35) may have distinct functions.…”

“…Mice were infected with 2 adenoviruses (5 × 10 8 pfu/ mouse) by intravenous injection 1 day before or 5 days after cell inoculation. Of the 2 adenovirus-5 variants, AdGFP expresses GFP, whereas AdASM expresses both ASM and GFP, because it contains a GFP sequence (27).…”

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…ASMase is overexpressed in the adipose tissue of ob/ob mice fed with methionine-and choline-deficient (MCD) diet, in the liver and serum samples from patients with NASH (65,121,125). An improvement in LDLr Ϫ/Ϫ /ASMase Ϫ/Ϫ mice were associated with a paradoxical increase in hepatic Cer levels and de novo Cer synthesis due to the increased SPT expression (69,131,135). ASMase deficiency interrupted the expression of ER stress markers after alcohol or HFD feeding (48,50,68).…”

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

“…SMPD1-immunoprecipitation and Western blotting of the enzyme were precipitated from diluted plasma with polyclonal anti-SMPD1 antibodies against the N-terminal epitope (H-181) conjugated to Agarose-beads (sc-11352, Santa Cruz Biotechnology Inc., N-17, sc-9816) (29). After washing and electrophoretic separation, proteins were transferred to polyvinylidene difluoride (PVDF) membranes.…”