title: 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.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan. osawa-gif@umin.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suetsugu
authors.forename: Kouichi
authors.initials: K
authors.lastname: Miura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Adachi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Yoshimune
authors.initials: Y
authors.lastname: Shiratori
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Banno
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Masahito
authors.initials: M
authors.lastname: Nagaki
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000096:biosynthesis; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; C495682:Slc2a2 protein, mouse; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D005947:Glucose