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EDITORIAL |
Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
Address all correspondence and requests for reprints to: Abhimanyu Garg, M.D., University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: Abhimanyu.garg{at}utsouthwestern.edu.
Caveolae are specialized plasma membrane microdomains appearing as 50- to 100-nm vesicular invaginations (1, 2). These organelles were initially identified by Yamada (3) more than 50 yr ago and can be found individually or in clusters at the surface of several cell types, including adipocytes, endothelial cells, fibroblasts, and myocytes. These plasma membrane domains, often referred to as lipid rafts, are rich in cholesterol, glycosphingolipids, and signaling proteins, especially caveolins. Caveolins are major components of the caveolae, and three members of this family (caveolins 1, 2, and 3) have been identified.
There is tissue-specific expression of caveolins. Caveolin-1 (CAV1) is ubiquitously expressed but more so in the adipocytes, endothelial cells, and fibroblasts (4). CAV2 is coexpressed with CAV1 and hetero-oligomerizes with it in many cell types (5). CAV3 expression is more restricted to the myocytes (6). CAV1 gene encodes two isoforms of CAV1, 
and β, using two alternate start sites (7). Although CAV1 contains residues 1–178, the β isoform is derived from translation at an alternate start site at an internal methionine at position 32. CAV1 has a transmembrane domain and a W-W (tryptophan-tryptophan) domain for interaction with other proteins. CAV1 is palmitoylated at the cysteine residues at the 133, 143, and 156 positions in the carboxy terminus for cholesterol binding and interaction with other caveolar components (8). The protein is inserted in the membrane in such a way that both its amino and carboxy termini are cytoplasmic.
Caveolins have been postulated to have a role in vesicular trafficking, homeostasis of cellular cholesterol, fatty acids and triglycerides, and signal transduction. To unravel the functions of caveolins, knockout mice have been generated for each CAV gene. In the case of Cav1, four independent groups have generated homozygous knockout mice (9, 10, 11, 12). In general, the Cav1–/– mice are viable and fertile but develop vascular dysfunction, thickened alveolar septa due to proliferation of endothelial cells and fibrosis, pulmonary hypertension, right ventricular hypertrophy, cardiomyopathy and increased susceptibility to tumorigenesis (9, 10, 11, 13, 14). Male Cav1–/– mice have hypercalciuria and urinary bladder stones (12). The Cav1–/– mice also have reduced sc and intraabdominal fat with underdeveloped perigonadal fat pads but not frank, generalized lipodystrophy (15). As early as 12 wk of age, female Cav1–/– mice show reduced sc and mammary gland fat, and male Cav1–/– mice have a slight reduction of periepididymal fat (15). Histopathology reveals nearly absent sc adipocytes in the hypodermal fat layer of Cav1–/– mice. Interestingly, brown adipose tissue is spared and undergoes hypertrophy (15). These null mice also develop hypertriglyceridemia, hypoleptinemia, and hypoadiponectinemia (15). Upon feeding a high-fat diet, the Cav1–/– mice do not gain as much body fat as the wild-type mice and develop postprandial hyperinsulinemia and insulin resistance (16). This phenotype is certainly reminiscent of partial lipodystrophy.
Several loci have been identified in the last few years for genetic lipodystrophies in humans including 1-acylglycerol-3-phosphate acyltransferase 2 (AGPAT2), Berardinelli-Seip congenital lipodystrophy 2 (BSCL2), lamin A/C (LMNA), zinc metalloprotease (ZMPSTE24), peroxisome-proliferator-activated receptor 
(PPARG) and v-AKT murine thymoma oncogene homolog 2 (AKT2) (17). In this issue of JCEM, Ae Kim et al. (18) add a new locus, CAV1, to this list and report the first patient with autosomal recessive, congenital generalized lipodystrophy (CGL or BSCL), who had a homozygous, G28X, null mutation in CAV1. This patient has some clinical features similar to those reported in patients with CGL, type 1 due to AGPAT2 mutations and type 2 due to BSCL2 gene mutations. As a young adult, this patient had near-complete absence of sc, intrathoracic, and intraabdominal fat. She also developed insulin resistance, acanthosis nigricans, hirsutism, diabetes mellitus, and hypertriglyceridemia during childhood and had marked hypoleptinemia and hypoadiponectinemia. However, she did have some clinical features distinct from other CGL patients. She had well-preserved bone marrow fat, which is not seen in both types of CGL (19), and had no lytic lesions in the appendicular skeleton after puberty, which are usually noted in CGL, type 1 (20). Trace amounts of sc fat in the dorsal cervical and thoracic region were observed on magnetic resonance images. Similar to patients with CGL type 1, preservation of mechanical adipose tissue in the retroorbital region and periarticular region and in the palms and soles was noted (21), but the scalp fat was decreased. The patient was reported to have facial lipodystrophy at 3 months of age. Because the lipodystrophy phenotype was not examined at birth, it remains unclear whether this is a classical case of CGL. There is a possibility that generalized lipodystrophy developed gradually over a period of time in this patient.
Among other peculiar clinical features of this patient was short stature, which is unusual in other types of CGL. She also had primary amenorrhea, although the precise reason for it was not investigated. Most likely it is related to polycystic ovarian syndrome instead of primary or secondary hypogonadism because the patient had well developed mammary tissue evident on axial magnetic resonance imaging of the chest as well as hirsutism. Another interesting clinical feature in the patient was hypocalcemia and hypomagnesemia, which were attributed to vitamin D resistance. However, this phenotype was not investigated fully and requires further investigation of mineral metabolism after discontinuation of calcitriol therapy. Interestingly, although this patient had reduced bone mass on radiographs, patients with CGL types 1 and 2 have increased bone density.
Caveolae are particularly abundant in adipocyte membranes occupying 30% of the surface area. There is a 10-fold increase in the number of caveolae during differentiation of 3T3-L1 cells to mature adipocytes (22). CAV1 has been identified as a major fatty acid-binding protein on the plasma membranes of the adipocytes that translocates to lipid droplets from the plasma membrane in response to free fatty acids (23), suggesting that CAV1 may play a role in the transport or storage of free fatty acids and triglycerides in lipid droplets (24, 25). Thus, CAV1-null mutation in this patient could have caused lipodystrophy by several mechanisms, including disruption of adipocyte differentiation, lipid transport through caveolae, and impaired formation of lipid droplets (Fig. 1
). On the other hand, AGPAT2 mutations cause lipodystrophy, which is likely due to lack of biosynthesis of triglycerides and phospholipids in the adipocytes or due to impaired adipocyte differentiation (17). Although precise mechanisms by which BSCL2 mutations cause lipodystrophy are not clear, recent studies on YLR404w (also known as Fld1p), a yeast homolog of BSCL2-encoded protein seipin, suggest its role in lipid droplet formation (26, 27).
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Ae Kim et al. (18) also report that none of the three confirmed subjects harboring the heterozygous null mutation, including the mother, a brother and a sister of the proband, had lipodystrophy, hyperinsulinemia, or hypertriglyceridemia. However, the father, an obligate heterozygote, had hypertension and hypercholesterolemia whereas the mother had type 2 diabetes and hypertension. On the other hand, Cao et al. (28) have reported heterozygous CAV1 mutations, I134fsdelA-X137 and –88delC, in two probands with partial lipodystrophy and hypertriglyceridemia. However, whether –88delC mutation in the 5'-untranslated region affects the transcription of CAV1 gene was not demonstrated. In addition, the patterns of lipodystrophy associated with the two heterozygous mutations were completely different. Indeed, the Cav1+/– mice do not show any phenotype. Thus, whether heterozygous mutations in CAV1 in humans have any functional consequences remains unclear.
The identification of CAV1 as a locus for human lipodystrophy certainly advances our knowledge in understanding the role of caveolae in lipid storage and synthesis in adipocytes. The availability of fibroblasts from CAV1-deficient subjects provides a unique opportunity to explore further the role of CAV1 in cell surface signaling and cellular differentiation. These studies may also elucidate how CAV1 deficiency causes lipodystrophy and associated metabolic derangements in humans.
Acknowledgments
We thank Sarah Mayhew for preparing the illustration.
Footnotes
This work was supported by the National Institutes of Health Grant R01-DK54387 and by the Southwestern Medical Foundation.
Abbreviations: CAV1, Caveolin-1; CGL, congenital generalized lipodystrophy.
Received February 25, 2008.
Accepted February 25, 2008.
References
This article has been cited by other articles:
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  M. Bastiani, L. Liu, M. M. Hill, M. P. Jedrychowski, S. J. Nixon, H. P. Lo, D. Abankwa, R. Luetterforst, M. Fernandez-Rojo, M. R. Breen, et al. MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes J. Cell Biol., June 29, 2009; 185(7): 1259 - 1273. [Abstract] [Full Text] [PDF]
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 S. Parker, D. S. Walker, S. Ly, and H. A. Baylis Caveolin-2 Is Required for Apical Lipid Trafficking and Suppresses Basolateral Recycling Defects in the Intestine of Caenorhabditis elegans Mol. Biol. Cell, March 15, 2009; 20(6): 1763 - 1771. [Abstract] [Full Text] [PDF]
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