Trends in Endocrinology & Metabolism
ReviewFat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes
Introduction
Although caveolae were first described as morphological features of the plasma membrane nearly 60 years ago, it was the discovery of caveolin-1 as an essential protein constituent that opened the floodgates for molecular studies of these structures [1]. Caveolin-1 proved to be identical to a 22-kDa protein that is the major tyrosine phosphorylated protein of src-transformed cells [2], an observation that suggested a link between cancer and caveolae. Despite the many years since these observations, the link between caveolae and cancer remains confusing and contradictory, with some studies supporting oncogenic properties for this protein and other studies suggesting tumor-suppressor activity [3]. These apparent contradictions illustrate the current status concerning caveolar functions, which on the one hand, have been extensively studied, but on the other hand, are far from understood and are controversial [4]. As a possible exception to this general statement, however, considerable in vivo and in vitro evidence supports a role for caveolae in adipocyte lipid metabolism, although many mechanistic details of this involvement remain uncertain, and these will be discussed below. Additional aspects of caveolae biology, such as recent advances in elucidating the nature of their protein composition and requirements for assembly have been reviewed in detail 5, 6, 7, 8 or described elsewhere [9], and will be briefly summarized below.
Section snippets
Caveolae structural components
The caveolins, the first known components of caveolae, comprise a family of three small (151–178 amino acids) integral membrane proteins with a 33 amino acid hydrophobic domain, roughly in the middle of the protein, which anchors them to the lipid bilayer by a loop structure that does not extend to the extracellular milieu [10]. Consequently, all the functions and interactions of caveolins are thought to be in the cytosol or in the inner leaflet of the plasma-membrane bilayer. The C terminus of
Caveolae deficiency and lipid metabolism in vivo
The role of caveolae in organismal lipid metabolism first became apparent with the generation of caveolin-1 knockout mice. These animals lack caveolae in non-muscle tissues, are lean with small adipocytes, are resistant to insulin, and exhibit defects in insulin signaling 32, 33. Mice lacking cavin-1 have a similar phenotype, being lean, hyperlipidemic and insulin-resistant, but unlike the caveolin-1 null mice, are markedly hyperinsulinemic at the age of 8–12 weeks [29]. As noted above, cavin-1
Caveolin, caveolae and lipid metabolism in vitro studies
As expected, the majority of caveolin-1 and -2 in adipocytes is found at the cell surface (90% or more) 45, 46, but a significant amount can be found intracellularly, as determined by cell fractionation of primary and cultured fat cells 45, 46, 47. Of course, the biosynthesis of integral plasma-membrane proteins such as caveolin involves their translation in the endoplasmic reticulum (ER) (see below) and transit through the Golgi apparatus, which might account in part for the observed
Other protein components of caveolae and lipid metabolism
Caveolae express cavin-1 at levels roughly comparable with caveolin-1, as suggested by immunogold double labeling of these proteins and EM [69], and the question arises as to whether or not cavin-1 can affect adipocyte lipid metabolism directly, or secondarily as a component of caveolae. Cavin-1 knockdown in vitro diminishes the acute uptake of labeled oleate [27], and the in vivo effects of cavin-1 loss are much more dramatic, resulting in small fat cells and lipodystrophy [29]. A recent paper
Conclusions and future directions
There is now a large body of data from in vitro and in vivo experimental approaches, as well as from experiments of nature, that support a role for caveolae in lipid trafficking and metabolism. The apparently identical phenotypes of mice with targeted deletions eliminating caveolae to that of humans with naturally occurring inactivating mutations of caveolar proteins provide ample proof-of-principle for the physiological importance of caveolae, and the use of a ‘model’ organism to gain insight
Acknowledgment
This work was supported by NIH grants R01DK056935 & R01DK030425 to P.F.P.
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