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Translocation of Glycosylphosphatidylinositol-Anchored Proteins from Plasma Membrane Microdomains to Lipid Droplets in Rat Adipocytes Is Induced by Palmitate, H₂O₂, and the Sulfonylurea Drug Glimepiride

Sanofi-Aventis Pharma Germany, Frankfurt am Main, Germany

Inhibition of lipolysis by palmitate, H₂O₂, and the antidiabetic sulfonylurea drug, glimepiride, in rat adipocytes has been shown previously to rely on the concerted degradation of cAMP by the glycosylphosphatidylinositol (GPI)-anchored phosphodiesterase Gce1 and 5'-nucleotidase CD73, which both gain access to the lipid droplets (LDs). The present report demonstrates the translocation of Gce1 and CD73, harboring the intact GPI anchor, from detergent-insoluble glycolipid-enriched plasma membrane domains (DIGs) to the LDs in response to palmitate, H₂O₂, and glimepiride by analysis of their steady-state distribution using photoaffinity labeling and activity determination as well as of their redistribution after pulse or equilibrium metabolic labeling. We were surprised to find that palmitate, H₂O₂, and glimepiride induced the activation of the GPI-specific phospholipase C (GPI-PLC) at DIGs of rat adipocytes, leading to anchorless Gce1 and CD73. Inhibition of the GPI-PLC or the presence of nonhydrolyzable substrate analogs of Gce1 and CD73 interfered with the palmitate-, H₂O₂-, and glimepiride-induced 1) lipolytic cleavage of Gce1 and CD73, 2) translocation of their GPI-anchored versions from DIGs to LDs, 3) up-regulation of cAMP degradation, and 4) inhibition of lipolysis. These data suggest a novel insulin-independent antilipolytic mechanism in rat adipocytes, which relies on the palmitate-, H₂O₂-, and glimepiride-induced and GPI-PLC-dependent translocation of (c)AMP-degrading GPI-anchored proteins from the adipocyte plasma membrane to LDs. The findings may shed new light on the biogenesis and degradation of LDs in response to physiological and pharmacological stimuli.

Address correspondence to: Dr. Günter Müller, Sanofi-Aventis Pharma Germany GmbH, TD Metabolism, Industrial Park Höchst, Bldg. H821, 65926 Frankfurt am Main, Germany. E-mail: guenter.mueller{at}sanofi-aventis.com

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