AMP-activated protein kinase suppresses biosynthesis of glucosylceramide by reducing intracellular sugar nucleotides

Yohei Ishibashi, Yoshio Hirabayashi

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The membrane glycolipid glucosylceramide (GlcCer) plays a critical role in cellular homeostasis. Its intracellular levels are thought to be tightly regulated. How cells regulate GlcCer levels remains to be clarified. AMP-activated protein kinase (AMPK), which is a crucial cellular energy sensor, regulates glucose and lipid metabolism to maintain energy homeostasis. Here, we investigated whether AMPK affects GlcCer metabolism. AMPK activators (5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside and metformin) decreased intracellular GlcCer levels and synthase activity in mouse fibro-blasts. AMPK inhibitors or AMPK siRNA reversed these effects, suggesting that GlcCer synthesis is negatively regulated by an AMPK-dependent mechanism. Although AMPK did not affect the phosphorylation or expression of GlcCer synthase, the amount of UDP-glucose, an activated form of glucose required for GlcCer synthesis, decreased under AMPK-activating conditions. Importantly, the UDP-glucose pyrophosphatase Nudt14, which degrades UDP-glucose, generating UMP and glucose 1-phosphate, was phosphorylated and activated by AMPK. On the other hand, suppression of Nudt14 by siRNA had little effect on UDP-glucose levels, indicating that mammalian cells have an alternative UDPglucose pyrophosphatase that mainly contributes to the reduction of UDP-glucose under AMPK-activating conditions. Because AMPK activators are capable of reducing GlcCer levels in cells from Gaucher disease patients, our findings suggest that reducing GlcCer through AMPK activation may lead to a new strategy for treating diseases caused by abnormal accumulation of GlcCer.

Original languageEnglish
Pages (from-to)18245-18260
Number of pages16
JournalJournal of Biological Chemistry
Volume290
Issue number29
DOIs
Publication statusPublished - Jul 17 2015
Externally publishedYes

Fingerprint

Glucosylceramides
AMP-Activated Protein Kinases
Biosynthesis
Sugars
Nucleotides
Uridine Diphosphate Glucose
ceramide glucosyltransferase
Small Interfering RNA
Homeostasis
Pyrophosphatases
Uridine Monophosphate
Glucose sensors
Glucose
Gaucher Disease
Phosphorylation
Metformin
Glycolipids
Protein Kinase Inhibitors
Lipid Metabolism
Metabolism

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

AMP-activated protein kinase suppresses biosynthesis of glucosylceramide by reducing intracellular sugar nucleotides. / Ishibashi, Yohei; Hirabayashi, Yoshio.

In: Journal of Biological Chemistry, Vol. 290, No. 29, 17.07.2015, p. 18245-18260.

Research output: Contribution to journalArticle

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