Regulation of adipocyte lipolysis by degradation of the perilipin protein: nelfinavir enhances lysosome-mediated perilipin proteolysis.
A decrease in the lipid droplet-associated protein perilipin may constitute a mechanism for enhanced adipocyte lipolysis under nonstimulated (basal) conditions, and increased basal lipolysis has been linked to whole body metabolic dysregulation. Here we investigated whether the lipolytic actions of the human immunodeficiency virus protease inhibitor, nelfinavir, are mediated by decreased perilipin protein content and studied the mechanisms by which it occurs. Time course analysis revealed that the decrease in perilipin protein content preceded the increase in lipolysis. A causative relationship was suggested by demonstrating that nelfinavir potently increased lipolysis in adipocytes derived from mouse embryonal fibroblasts expressing perilipin but not in mouse embryonal fibroblast adipocytes devoid of perilipin and that adenoviral mediated overexpression of perilipin in 3T3-L1 adipocytes blocked the lipolytic actions of nelfinavir. Nelfinavir did not alter mRNA content of perilipin but rather decreased perilipin proteins t((1/2)) from >70 to 12 h. Protein degradation of perilipin in both control and nelfinavir-treated adipocytes could be prevented by inhibiting lysosomal proteolysis using leupeptin or NH(4)Cl but not by the proteasome inhibitor MG-132. We propose that proteolysis of perilipin involving the lysosomal protein degradation machinery may constitute a novel mechanism for enhancing adipocyte lipolysis.
Kovsan
Julia
J
Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.
Ben-Romano
Ronit
R
Souza
Sandra C
SC
Greenberg
Andrew S
AS
Rudich
Assaf
A
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008066:Lipolysis / Q000187:drug effects*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism; D051379:Mice; D019888:Nelfinavir / Q000494:pharmacology*; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction
D002352:Carrier Proteins; D017320:HIV Protease Inhibitors; D000070778:Perilipin-1; D010750:Phosphoproteins; D049452:Green Fluorescent Proteins; D008715:Methionine; D019888:Nelfinavir