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Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.

http://www.ncbi.nlm.nih.gov/pubmed/16595669

Hormone-sensitive lipase (HSL) is the predominant lipase effector of catecholamine-stimulated lipolysis in adipocytes. HSL-dependent lipolysis in response to catecholamines is mediated by protein kinase A (PKA)-dependent phosphorylation of perilipin A (Peri A), an essential lipid droplet (LD)-associated protein. It is believed that perilipin phosphorylation is essential for the translocation of HSL from the cytosol to the LD, a key event in stimulated lipolysis. Using adipocytes retrovirally engineered from murine embryonic fibroblasts of perilipin null mice (Peri-/- MEF), we demonstrate by cell fractionation and confocal microscopy that up to 50% of cellular HSL is LD-associated in the basal state and that PKA-stimulated HSL translocation is fully supported by adenoviral expression of a mutant perilipin lacking all six PKA sites (Peri Adelta1-6). PKA-stimulated HSL translocation was confirmed in differentiated brown adipocytes from perilipin null mice expressing an adipose-specific Peri Adelta1-6 transgene. Thus, PKA-induced HSL translocation was independent of perilipin phosphorylation. However, Peri Adelta1-6 failed to enhance PKA-stimulated lipolysis in either MEF adipocytes or differentiated brown adipocytes. Thus, the lipolytic action(s) of HSL at the LD surface requires PKA-dependent perilipin phosphorylation. In Peri-/- MEF adipocytes, PKA activation significantly enhanced the amount of HSL that could be cross-linked to and co-immunoprecipitated with ectopic Peri A. Notably, this enhanced cross-linking was blunted in Peri-/- MEF adipocytes expressing Peri Adelta1-6. This suggests that PKA-dependent perilipin phosphorylation facilitates (either direct or indirect) perilipin interaction with LD-associated HSL. These results redefine and expand our understanding of how perilipin regulates HSL-mediated lipolysis in adipocytes.

Pubmed ID: 16595669 RIS Download

Mesh terms: Adipocytes | Animals | Base Sequence | Carrier Proteins | Cell Line | Cyclic AMP-Dependent Protein Kinases | DNA Primers | Electrophoresis, Polyacrylamide Gel | Lipolysis | Mice | Mice, Inbred C57BL | Mice, Knockout | Microscopy, Fluorescence | Phosphoproteins | Phosphorylation | Sterol Esterase | Subcellular Fractions

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Associated grants

  • Agency: NIA NIH HHS, Id: AG024635
  • Agency: NIDDK NIH HHS, Id: IH DK-50647
  • Agency: NIDDK NIH HHS, Id: P30 DK-34928
  • Agency: NINDS NIH HHS, Id: P30 NS047243

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