Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling

Jose Antonio Chavez, William L. Holland, Julia Bär, Konrad Sandhoff, Scott A. Summers

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Recent studies indicate that insulin resistance and type 2 diabetes result from the accumulation of lipids in tissues not suited for fat storage, such as skeletal muscle and the liver. To elucidate the mechanisms linking exogenous fats to the inhibition of insulin action, we evaluated the effects of free fatty acids (FFAs) on insulin signal transduction in cultured C2C12 myotubes. As we described previously (Chavez, J. A., and Summers, S. A. (2003) Arch. Biochem. Biophys. 419, 101-109), long-chain saturated FFAs inhibited insulin stimulation of Akt/protein kinase B, a central regulator of glucose uptake and anabolic metabolism. Moreover, these FFAs stimulated the de novo synthesis of ceramide and sphingosine, two sphingolipids shown previously to inhibit insulin action. To determine the contribution of either sphingolipid in FFA-dependent inhibition of insulin action, we generated C2C12 myotubes that constitutively overexpress acid ceramidase (AC), an enzyme that catalyzes the lysosomal conversion of ceramide to sphingosine. AC overexpression negated the inhibitory effects of saturated FFAs on insulin signaling while blocking their stimulation of ceramide accumulation. By contrast, AC overexpression stimulated the accrual of sphingosine. These results support a role for aberrant accumulation of ceramide, but not sphingosine, in the inhibition of muscle insulin sensitivity by exogenous FFAs.

Original languageEnglish (US)
Pages (from-to)20148-20153
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number20
DOIs
StatePublished - May 20 2005

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Acid Ceramidase
Nonesterified Fatty Acids
Sphingosine
Fatty Acids
Ceramides
Insulin
Sphingolipids
Skeletal Muscle Fibers
Insulin Resistance
Fats
Muscle
Proto-Oncogene Proteins c-akt
Signal transduction
Type 2 Diabetes Mellitus
Signal Transduction
Skeletal Muscle
Arches
Medical problems
Metabolism
Liver

ASJC Scopus subject areas

  • Biochemistry

Cite this

Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. / Chavez, Jose Antonio; Holland, William L.; Bär, Julia; Sandhoff, Konrad; Summers, Scott A.

In: Journal of Biological Chemistry, Vol. 280, No. 20, 20.05.2005, p. 20148-20153.

Research output: Contribution to journalArticle

Chavez, Jose Antonio ; Holland, William L. ; Bär, Julia ; Sandhoff, Konrad ; Summers, Scott A. / Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 20. pp. 20148-20153.
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