Perilipin Promotes Hormone-sensitive Lipase-mediated Adipocyte Lipolysis via Phosphorylation-dependent and -independent Mechanisms

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)-associ...

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Published in:The Journal of biological chemistry 2006-06, Vol.281 (23), p.15837-15844
Main Authors: Miyoshi, Hideaki, Souza, Sandra C., Zhang, Hui-Hong, Strissel, Katherine J., Christoffolete, Marcelo A., Kovsan, Julia, Rudich, Assaf, Kraemer, Fredric B., Bianco, Antonio C., Obin, Martin S., Greenberg, Andrew S.
Format: Article
Language:English
Subjects:
Adipocytes - metabolism
Animals
Base Sequence
Carrier Proteins
Cell Line
Cyclic AMP-Dependent Protein Kinases - metabolism
DNA Primers
Electrophoresis, Polyacrylamide Gel
Lipolysis - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Fluorescence
Perilipin-1
Phosphoproteins - physiology
Phosphorylation
Sterol Esterase - physiology
Subcellular Fractions - metabolism
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Summary: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 AΔ1–6). PKA-stimulated HSL translocation was confirmed in differentiated brown adipocytes from perilipin null mice expressing an adipose-specific Peri AΔ1–6 transgene. Thus, PKA-induced HSL translocation was independent of perilipin phosphorylation. However, Peri AΔ1–6 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 AΔ1–6. 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M601097200