Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation.
Recently, it was shown that caveolin-1 can be redirected from the cell surface to intracellular lipid droplets in a variety of cell types. Here, we directly address the role of caveolin-1 in lipid droplet formation and breakdown, showing that caveolin-1 null mice exhibit markedly attenuated lipolytic activity. Mechanistically, although the activity of protein kinase A (PKA) was greatly increased in caveolin-1 null adipocytes, the phosphorylation of perilipin was dramatically reduced, indicating that caveolin-1 may facilitate the PKA-mediated phosphorylation of perilipin. In support of this hypothesis, coimmunoprecipitation experiments revealed that treatment with a beta(3)-adrenergic receptor agonist resulted in ligand-induced complex formation between perilipin, caveolin-1, and the catalytic subunit of PKA in wild-type but not in caveolin-1 null fat pads. We also show that caveolin-1 expression is important for efficient lipid droplet formation because caveolin-1 null embryonic fibroblasts stably transfected with perilipin accumulated approximately 4.5-fold less lipid than perilipin-transfected wild-type cells. Finally, high-pressure freeze-substitution electron microscopy of adipose tissue revealed dramatic perturbations in the architecture of the "lipid droplet cortex" (the interface between the lipid droplet surface and the cytoplasm) in caveolin-1 null perigonadal adipocytes. Taken together, our data provide the first molecular genetic evidence that caveolin-1 plays a critical functional and structural role in the modulation of both lipid droplet biogenesis and metabolism in vivo.
Cohen
Alex W
AW
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Razani
Babak
B
Schubert
William
W
Williams
Terence M
TM
Wang
Xiao Bo
XB
Iyengar
Puneeth
P
Brasaemle
Dawn L
DL
Scherer
Philipp E
PE
Lisanti
Michael P
MP
D017667:Adipocytes / Q000378:metabolism / Q000648:ultrastructure; D000273:Adipose Tissue / Q000378:metabolism; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins; D051242:Caveolin 1; D022461:Caveolins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D005215:Fasting / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D050356:Lipid Metabolism; D008055:Lipids / Q000502:physiology*; D008066:Lipolysis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron / Q000379:methods; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D013997:Time Factors; D015854:Up-Regulation
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D004149:Dioxoles; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D000070778:Perilipin-1; D010750:Phosphoproteins; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D017868:Cyclic AMP-Dependent Protein Kinases