Role of Caveolin-1 in the Modulation of Lipolysis and Lipid Droplet Formation

Abstract

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 ␤ 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 ϳ4.5-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.

Caveolin-2 Is Required for Apical Lipid Trafficking and Suppresses Basolateral Recycling Defects in the Intestine ofCaenorhabditis elegans

“…These results suggest that cav-2 is required for normal lipid uptake in the intestine. This function is reminiscent of the importance of caveolin function to lipid metabolism in mammals (Cohen et al, 2004b;Le Lay and Kurzchalia, 2005;Martin and Parton, 2005;Le Lay et al, 2006;Parton and Simons, 2007;Garg and Agarwal, 2008;Heimerl et al, 2008;Kim et al, 2008b). Caveolae and CAV1 are highly concentrated in mammalian adipocytes, and it has become clear that caveolae are an important part of the trafficking system that regulates the homeostasis of lipids in adipocytes and the formation of lipid bodies.…”

“…These include defects in lipid homeostasis (Cohen et al, 2004a;Le Lay and Kurzchalia, 2005;Martin and Parton, 2005;Parton and Simons, 2007). Central to the defects in lipid homeostasis is the role of caveolin-1 in endocytosis in adipocytes (Cohen et al, 2004b;Martin and Parton, 2005;Le Lay et al, 2006). Mutations in caveolin-1 have also been shown to be associated with the rare lipodystrophies: Berardinelli-Seip congenital lipodystrophy (OMIM:269700) and an atypical partial lipodystrophy and hypertriglyceridemia (Cao et al, 2008;Kim et al, 2008a).…”

Caveolin-1 Gene Disruption Promotes Mammary Tumorigenesis and Dramatically Enhances Lung Metastasis in Vivo

“…Therefore, we elected to transform previously generated immortalized fibroblastic cell lines (34,35) with the PyMT oncogene. These immortalized MEFs were generated from wildtype and Cav-1 (Ϫ/Ϫ)-null mice and, therefore, either endogenously express or completely lack caveolin-1.…”

Loss of Caveolin-1 Impairs Retinal Function Due to Disturbance of Subretinal Microenvironment

“…Progress in understanding the function(s) of Cav-1 has resulted from investigations of mice in which Cav-1 has been ablated (15)(16)(17)(18). Global deletion of Cav-1 results in loss of morphologically identifiable caveolae and a variety of abnormalities, including microvessel hyperpermeability (19), alterations in lipid metabolism (20,21), and insulin resistance (22). Recently, dysregulation of or abnormalities in Cav-1 have been linked to diabetic retinopathy (23) and inflamed uveitic retinas (24).…”