Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism

Ping Liu, Brian J. Leffler, Lara K. Weeks, Guoli Chen, Christine M. Bouchard, Andrew B. Strawbridge, Jeffrey Elmendorf

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

A basis for the insulin mimetic effect of sphingomyelinase on glucose transporter isoform GLUT4 translocation remains unclear. Because sphingomyelin serves as a major determinant of plasma membrane cholesterol and a relationship between plasma membrane cholesterol and GLUT4 levels has recently become apparent, we assessed whether GLUT4 translocation induced by sphingomyelinase resulted from changes in membrane cholesterol content. Exposure of 3T3-L1 adipocytes to sphingomyelinase resulted in a time-dependent loss of sphingomyelin from the plasma membrane and a concomitant time-dependent accumulation of plasma membrane GLUT4. Degradation products of sphingomyelin did not mimic this stimulatory action. Plasma membrane cholesterol amount was diminished in cells exposed to sphingomyelinase. Restoration of membrane cholesterol blocked the stimulatory effect of sphingomyelinase. Increasing concentrations of methyl-β-cyclodextrin, which resulted in a dose-dependent reversible decrease in membrane cholesterol, led to a dose-dependent reversible increase in GLUT4 incorporation into the plasma membrane. Although increased plasma membrane GLUT4 content by cholesterol extraction with concentrations of methyl-β-cyclodextrin above 5 mM most likely reflected decreased GLUT4 endocytosis, translocation stimulated by sphingomyelinase or concentrations of methyl-β-cyclodextrin below 2.5 mM occurred without any visible changes in the endocytic retrieval of GLUT4. Furthermore, moderate loss of cholesterol induced by sphingomyelinase or low concentrations of methyl-β-cyclodextrin did not alter membrane integrity or increase the abundance of other plasma membrane proteins such as the GLUT1 glucose transporter or the transferrin receptor. Regulation of GLUT4 translocation by moderate cholesterol loss did not involve known insulin-signaling proteins. These data reveal that sphingomyelinase enhances GLUT4 exocytosis via a novel cholesterol-dependent mechanism.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume286
Issue number2 55-2
StatePublished - Feb 2004

Fingerprint

Sphingomyelin Phosphodiesterase
Cell membranes
Cholesterol
Cell Membrane
Cyclodextrins
Sphingomyelins
Membranes
Facilitative Glucose Transport Proteins
Insulin
Transferrin Receptors
Exocytosis
Endocytosis
Adipocytes
Restoration
Blood Proteins
Protein Isoforms
Membrane Proteins

Keywords

  • Signal transduction
  • Sphingolipids
  • Vesicular trafficking

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Liu, P., Leffler, B. J., Weeks, L. K., Chen, G., Bouchard, C. M., Strawbridge, A. B., & Elmendorf, J. (2004). Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism. American Journal of Physiology - Cell Physiology, 286(2 55-2).

Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism. / Liu, Ping; Leffler, Brian J.; Weeks, Lara K.; Chen, Guoli; Bouchard, Christine M.; Strawbridge, Andrew B.; Elmendorf, Jeffrey.

In: American Journal of Physiology - Cell Physiology, Vol. 286, No. 2 55-2, 02.2004.

Research output: Contribution to journalArticle

Liu, P, Leffler, BJ, Weeks, LK, Chen, G, Bouchard, CM, Strawbridge, AB & Elmendorf, J 2004, 'Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism', American Journal of Physiology - Cell Physiology, vol. 286, no. 2 55-2.
Liu P, Leffler BJ, Weeks LK, Chen G, Bouchard CM, Strawbridge AB et al. Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism. American Journal of Physiology - Cell Physiology. 2004 Feb;286(2 55-2).
Liu, Ping ; Leffler, Brian J. ; Weeks, Lara K. ; Chen, Guoli ; Bouchard, Christine M. ; Strawbridge, Andrew B. ; Elmendorf, Jeffrey. / Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism. In: American Journal of Physiology - Cell Physiology. 2004 ; Vol. 286, No. 2 55-2.
@article{76f215a2b891411dabdbf6a5a003cbf8,
title = "Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism",
abstract = "A basis for the insulin mimetic effect of sphingomyelinase on glucose transporter isoform GLUT4 translocation remains unclear. Because sphingomyelin serves as a major determinant of plasma membrane cholesterol and a relationship between plasma membrane cholesterol and GLUT4 levels has recently become apparent, we assessed whether GLUT4 translocation induced by sphingomyelinase resulted from changes in membrane cholesterol content. Exposure of 3T3-L1 adipocytes to sphingomyelinase resulted in a time-dependent loss of sphingomyelin from the plasma membrane and a concomitant time-dependent accumulation of plasma membrane GLUT4. Degradation products of sphingomyelin did not mimic this stimulatory action. Plasma membrane cholesterol amount was diminished in cells exposed to sphingomyelinase. Restoration of membrane cholesterol blocked the stimulatory effect of sphingomyelinase. Increasing concentrations of methyl-β-cyclodextrin, which resulted in a dose-dependent reversible decrease in membrane cholesterol, led to a dose-dependent reversible increase in GLUT4 incorporation into the plasma membrane. Although increased plasma membrane GLUT4 content by cholesterol extraction with concentrations of methyl-β-cyclodextrin above 5 mM most likely reflected decreased GLUT4 endocytosis, translocation stimulated by sphingomyelinase or concentrations of methyl-β-cyclodextrin below 2.5 mM occurred without any visible changes in the endocytic retrieval of GLUT4. Furthermore, moderate loss of cholesterol induced by sphingomyelinase or low concentrations of methyl-β-cyclodextrin did not alter membrane integrity or increase the abundance of other plasma membrane proteins such as the GLUT1 glucose transporter or the transferrin receptor. Regulation of GLUT4 translocation by moderate cholesterol loss did not involve known insulin-signaling proteins. These data reveal that sphingomyelinase enhances GLUT4 exocytosis via a novel cholesterol-dependent mechanism.",
keywords = "Signal transduction, Sphingolipids, Vesicular trafficking",
author = "Ping Liu and Leffler, {Brian J.} and Weeks, {Lara K.} and Guoli Chen and Bouchard, {Christine M.} and Strawbridge, {Andrew B.} and Jeffrey Elmendorf",
year = "2004",
month = "2",
language = "English",
volume = "286",
journal = "American Journal of Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "2 55-2",

}

TY - JOUR

T1 - Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism

AU - Liu, Ping

AU - Leffler, Brian J.

AU - Weeks, Lara K.

AU - Chen, Guoli

AU - Bouchard, Christine M.

AU - Strawbridge, Andrew B.

AU - Elmendorf, Jeffrey

PY - 2004/2

Y1 - 2004/2

N2 - A basis for the insulin mimetic effect of sphingomyelinase on glucose transporter isoform GLUT4 translocation remains unclear. Because sphingomyelin serves as a major determinant of plasma membrane cholesterol and a relationship between plasma membrane cholesterol and GLUT4 levels has recently become apparent, we assessed whether GLUT4 translocation induced by sphingomyelinase resulted from changes in membrane cholesterol content. Exposure of 3T3-L1 adipocytes to sphingomyelinase resulted in a time-dependent loss of sphingomyelin from the plasma membrane and a concomitant time-dependent accumulation of plasma membrane GLUT4. Degradation products of sphingomyelin did not mimic this stimulatory action. Plasma membrane cholesterol amount was diminished in cells exposed to sphingomyelinase. Restoration of membrane cholesterol blocked the stimulatory effect of sphingomyelinase. Increasing concentrations of methyl-β-cyclodextrin, which resulted in a dose-dependent reversible decrease in membrane cholesterol, led to a dose-dependent reversible increase in GLUT4 incorporation into the plasma membrane. Although increased plasma membrane GLUT4 content by cholesterol extraction with concentrations of methyl-β-cyclodextrin above 5 mM most likely reflected decreased GLUT4 endocytosis, translocation stimulated by sphingomyelinase or concentrations of methyl-β-cyclodextrin below 2.5 mM occurred without any visible changes in the endocytic retrieval of GLUT4. Furthermore, moderate loss of cholesterol induced by sphingomyelinase or low concentrations of methyl-β-cyclodextrin did not alter membrane integrity or increase the abundance of other plasma membrane proteins such as the GLUT1 glucose transporter or the transferrin receptor. Regulation of GLUT4 translocation by moderate cholesterol loss did not involve known insulin-signaling proteins. These data reveal that sphingomyelinase enhances GLUT4 exocytosis via a novel cholesterol-dependent mechanism.

AB - A basis for the insulin mimetic effect of sphingomyelinase on glucose transporter isoform GLUT4 translocation remains unclear. Because sphingomyelin serves as a major determinant of plasma membrane cholesterol and a relationship between plasma membrane cholesterol and GLUT4 levels has recently become apparent, we assessed whether GLUT4 translocation induced by sphingomyelinase resulted from changes in membrane cholesterol content. Exposure of 3T3-L1 adipocytes to sphingomyelinase resulted in a time-dependent loss of sphingomyelin from the plasma membrane and a concomitant time-dependent accumulation of plasma membrane GLUT4. Degradation products of sphingomyelin did not mimic this stimulatory action. Plasma membrane cholesterol amount was diminished in cells exposed to sphingomyelinase. Restoration of membrane cholesterol blocked the stimulatory effect of sphingomyelinase. Increasing concentrations of methyl-β-cyclodextrin, which resulted in a dose-dependent reversible decrease in membrane cholesterol, led to a dose-dependent reversible increase in GLUT4 incorporation into the plasma membrane. Although increased plasma membrane GLUT4 content by cholesterol extraction with concentrations of methyl-β-cyclodextrin above 5 mM most likely reflected decreased GLUT4 endocytosis, translocation stimulated by sphingomyelinase or concentrations of methyl-β-cyclodextrin below 2.5 mM occurred without any visible changes in the endocytic retrieval of GLUT4. Furthermore, moderate loss of cholesterol induced by sphingomyelinase or low concentrations of methyl-β-cyclodextrin did not alter membrane integrity or increase the abundance of other plasma membrane proteins such as the GLUT1 glucose transporter or the transferrin receptor. Regulation of GLUT4 translocation by moderate cholesterol loss did not involve known insulin-signaling proteins. These data reveal that sphingomyelinase enhances GLUT4 exocytosis via a novel cholesterol-dependent mechanism.

KW - Signal transduction

KW - Sphingolipids

KW - Vesicular trafficking

UR - http://www.scopus.com/inward/record.url?scp=0742323128&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0742323128&partnerID=8YFLogxK

M3 - Article

C2 - 14522816

AN - SCOPUS:0742323128

VL - 286

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1857

IS - 2 55-2

ER -