Chanarin–Dorfman syndrome: Deficiency in CGI-58, a lipid droplet-bound coactivator of lipase

doi:10.1016/j.bbalip.2008.10.012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1791, Issue 6, June 2009, Pages 519-523

https://doi.org/10.1016/j.bbalip.2008.10.012 Get rights and content

Abstract

Chanarin–Dorfman syndrome (CDS) is a rare autosomal recessive disease of lipid metabolism; it is associated with congenital ichthyosis typed as non-bullous congenital ichthyosiform erythroderma (NCIE). CDS is characterized by the presence of an abnormally large number of cytosolic lipid droplets containing triacylglycerol (TG) in various tissues such as the skin, liver, and leukocytes. Mutations in the CGI-58 (also called ABHD5) gene encoding a 39-kDa protein of the α/β hydrolase domain subfamily have been shown to be responsible for this disorder. In adipocytes, CGI-58 is involved in TG degradation on lipid droplets; in doing so, it coordinates with several lipolytic factors including perilipin, a member of the PAT protein family, and ATGL, a putative rate-limiting lipase in adipocytes. In quiescent adipocytes, CGI-58 interacts with perilipin on the surfaces of lipid droplets. Upon hormonal stimulation, CGI-58 facilitates massive lipolysis by activating ATGL. Some CGI-58 mutations found in CDS patients cancel the ability to interact with perilipin or activate ATGL, indicating that the loss of these interactions is physiologically important. However, based on the tissue distributions of these lipolytic factors, there are likely multiple molecular targets of CGI-58 actions. This in turn gives rise to the multiple phenotypes of CDS, such as ichthyosis, liver steatosis, or neurosensory diseases.

Introduction

Lipid droplets are structures for neutral lipid storage, surrounded by a phospholipid monolayer [1], [2]. They are now recognized to be functional subcellular organelles rather than metabolically inactive lipid depots. Lipid droplets are involved in multiple intracellular processes such as lipid metabolism, cell signaling, and vesicle traffic; hence, they play important roles in body lipid homeostasis [3], [4]. In clinical fields, it has long been known that lipid droplet functions are linked to disorders such as obesity, inflammation, and atherosclerosis. On the other hand, recent studies have revealed that lipid droplet functions are regulated by the protein components associated with their surfaces. Surprisingly, however, there is little evidence of a direct relationship between a particular disease and a lipid droplet-associated protein. The current review focuses on recent findings vis-à-vis the functions of a lipid-droplet protein, CGI-58, a deficiency of which causes the neutral lipid storage disease, Chanarin–Dorfman syndrome (CDS).

Section snippets

Neutral lipid storage disease

In 1953, Jordans [5] described the occurrence of fat-containing vacuoles in the leukocytes of peripheral blood in two brothers, both of whom had progressive muscular dystrophy. These vacuolated leukocytes are often referred to as “Jordans' anomaly.” In 1966, Rozenszajn et al. [6] reported the same symptom in two sisters suffering from ichthyosis. Vacuoles were observed in the leukocytes of both sisters; in the bone marrow, vacuoles were found in the cells of the myeloid series. Cytochemical

Symptoms of CDS

CDS is a storage disease characterized by the deposition of neutral lipids in multiple organs, including leukocytes, liver, muscle, intestinal mucosa, and skin. A diagnosis of CDS is based on a characteristic spectrum of clinical and histochemical features. Abnormal lipid accumulation in the skin is detected by histochemical and electron microscopy techniques, revealing the occurrence of lipid droplets in the epidermis, particularly in the basal and granular layers [8], [9]. A diagnosis is

Biochemical studies

The TG contents of cultured cells from CDS lymphocytes, macrophages, and fibroblasts are two- to 20-fold higher in normal cells [12], [13], [14]. Even when cultured in lipid-deficient media, CDS cells exhibit a significant accumulation of cytoplasmic TG [14], [15], [16]. However, biochemical experiments did not reveal any abnormalities in the pathways of fatty acid uptake, transport, and β-oxidation. In addition, the activities of various enzymes, lipases, and carboxyesterases, as well as

Identification of CGI-58 as the responsible gene of CDS

Autosomal recessive ichthyosis (ARI) includes a heterogeneous group of disorders of keratinization, characterized by desquamation over the entire body. Some causal genes for ARI have been mapped and identified. For example, mutations in keratinocyte transglutaminase TGM1 on chromosome 14 have been found to be associated with lamellar ichthyosis in a subset of patients [23], [24], [25]. In 2000, Fischer et al. [26] performed a genome-wide scan of large, consanguineous families, through the use

CGI-58 mutations

The mutations identified by Lefèvre et al. [10] included splice-site mutations in two families (in exons 3 and 6), amino acid substitutions in three families (amino acid residues 7, 130, and 260), a nonsense mutation in the codon for amino acid residue 33, a deletion (46/47delAG), and an insertion (594insC). Since the study of Lefèvre et al., sequencing of CGI-58 has been performed for cases diagnosed with CDS, thus revealing a variety of mutations. A Japanese patient is homozygous for a novel

Structure of CGI-58

The genes named CGIs were identified by a comparative-gene-identification approach, to assist in human ortholog gene detection; in the process, an entire Caenorhabditis elegans proteome is applied as an alignment template [30]. CGI-58 is also known as α/β hydrolase domain-containing protein 5 (ABHD5). CGI-58 is widely expressed in various tissues, including skin, lymphocytes, liver, skeletal muscle, and the brain. This broad pattern of expression accords with the clinical phenotypes of CDS. The

Interaction of CGI-58 with perilipin on lipid droplets

Although CGI-58 is distributed in various tissues, it is expressed at a higher level in mature adipocytes. Recently, the physiological function of CGI-58 in adipocytes has been analyzed, and the results thereof suggest its active involvement in lipolysis.

In mammals, excess energy is stored as TG in the lipid droplets of adipose tissue; it is then supplied, on demand, to various tissues as fatty acids. Lipolysis, a precisely controlled process whereby TG is hydrolyzed, releasing fatty acids into

Physiological function of CGI-58

CGI-58 contains a canonical lipase motif, although the usual catalytic serine is replaced by asparagine. As expected, in vitro studies have shown that CGI-58 itself does not have a lipase/esterase activity [49], [50]. On the other hand, a siRNA-mediated knockdown of CGI-58 caused an abnormal accumulation of lipid droplets in 3T3-L1 preadipocytes and Hepa1 hepatoma cells, indicating reduced TG degradation [50]. Lass et al. [49] demonstrated that CGI-58 serves as a coactivator of ATGL, but not

Functions of CGI-58 in the etiology of CDS

CDS involves many organs and tissues, and causes ichthyosis, liver steatosis, and neurosensory effects, among other disorders. CGI-58 is expressed ubiquitously, thereby substantiating the systemic nature of CDS. On the other hand, perilipin, a binding partner for CGI-58, is not expressed in non-adipose tissues. Moreover, the expression of ATGL is limited–if it exists at all–in the liver, though there is some controversy owing to conflicting reports. Therefore, the aforementioned model involving

Concluding remarks

CGI-58, the gene responsible for CDS, is a key molecule for TG degradation in almost all human cell types. However, the molecular mechanisms of underpinning the actions of this protein may not be uniform, and the multiple targets of CGI-58 seem to determine the multiple phenotypes of CDS, such as ichthyosis, liver steatosis, and neurosensory diseases. Further understanding of the mechanism of CGI-58-driven TG hydrolysis in each cell type, including perilipin or ATGL-independent actions, should

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ReviewChanarin–Dorfman syndrome: Deficiency in CGI-58, a lipid droplet-bound coactivator of lipase

Abstract

Introduction

Section snippets

Neutral lipid storage disease

Symptoms of CDS

Biochemical studies

Identification of CGI-58 as the responsible gene of CDS

CGI-58 mutations

Structure of CGI-58

Interaction of CGI-58 with perilipin on lipid droplets

Physiological function of CGI-58

Functions of CGI-58 in the etiology of CDS

Concluding remarks

Trends Biochem. Sci.

J. Biol. Chem.

Prog. Lipid Res.

Curr. Biol.

Blood

J. Am. Acad. Dermatol.

J. Am. Acad. Dermatol.

Am. J. Hum. Genet.

Biochim. Biophys. Acta

FEBS Lett.

FEBS Lett.

Biochim. Biophys. Acta

J. Lipid Res.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Hum. Genet.

J. Invest. Dermatol.

J. Pediatr.

Methods Enzymol.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell. Metab.

J. Biol. Chem.

Review
Chanarin–Dorfman syndrome: Deficiency in CGI-58, a lipid droplet-bound coactivator of lipase