<i>CGI‐58/ABHD5</i> gene is mutated in Dorfman–Chanarin syndrome

Caux, F.; Selma, Zied Ben; Laroche, Liliane; Prud’homme, Jean François; Fischer, Judith

doi:10.1002/ajmg.a.30228

Cited by 16 publications

(11 citation statements)

References 9 publications

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“…Interaction with Mldp-Certain point mutations of ABHD5 produce a neutral lipid storage disease in humans (9,27), and one such mutation (E260K) was found to disrupt the interaction of ABHD5 with perilipin (13). We examined the effects of the homologous mutation in mouse Abhd5 (E262K) on interactions with Mldp.…”

Section: E262k Mutation Of Mouse Abhd5 Disrupts Itsmentioning

confidence: 99%

Functional Interactions between Mldp (LSDP5) and Abhd5 in the Control of Intracellular Lipid Accumulation

Granneman

Moore²,

Mottillo

et al. 2009

Journal of Biological Chemistry

124

150

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Cellular lipid metabolism is regulated in part by protein-protein interactions near the surface of intracellular lipid droplets. This work investigated functional interactions between Abhd5, a protein activator of the lipase Atgl, and Mldp, a lipid droplet scaffold protein that is highly expressed in oxidative tissues. Abhd5 was highly targeted to individual lipid droplets containing Mldp in microdissected cardiac muscle fibers. Mldp bound Abhd5 in transfected fibroblasts and directed it to lipid droplets in proportion to Mldp concentration. Analysis of protein-protein interactions in situ demonstrated that the interaction of Abhd5 and Mldp occurs mainly, if not exclusively, on the surface of lipid droplets. Oleic acid treatment rapidly increased the interaction between Abhd5 and Mldp, and this effect was suppressed by pharmacological inhibition of triglyceride synthesis. The functional role of the Abhd5-Mldp interaction was explored using a mutant of mouse Abhd5 (E262K) that has greatly reduced binding to Mldp. Mldp promoted the subcellular colocalization and interaction of Atgl with wild type, but not mutant, Abhd5. This differential interaction was reflected in cellular assays of Atgl activity. In the absence of Mldp, wild type and mutant Abhd5 were equally effective in reducing lipid droplet formation. In contrast, mutant Abhd5 was unable to prevent lipid droplet accumulation in cells expressing Mldp despite considerable targeting of Atgl to lipid droplets containing Mldp. These results indicate that the interaction between Abhd5 and Mldp is dynamic and essential for regulating the activity of Atgl at lipid droplets containing Mldp.Growing evidence indicates that lipogenesis and lipolysis are regulated by protein-protein interactions that occur on the surface of specialized intracellular lipid droplets (1, 2). PAT 3 (perilipin, adipophilin, and TIP-47) proteins, are thought to be key regulators of these processes by serving as scaffolds that organize and regulate the protein trafficking at lipid droplet surfaces (1-3). Mldp (muscle lipid droplet protein; alternatively, OXPAT, LSDP5) is a PAT family member that is highly expressed in tissues, like muscle and liver, having high oxidative capacity (4 -6). Expression of Mldp is up-regulated under conditions such as fasting and diabetes, in which the systemic supply of lipid to target tissues is increased, and in vitro studies suggest that Mldp plays a role in facilitating triglyceride storage as well as fatty acid oxidation (4 -6). It is not presently known how Mldp is involved in these functions, but we hypothesize that it is likely to involve direct or indirect interactions with lipases and lipase co-activators (3, 7). Abhd5 (␣/␤ hydrolase domain-containing protein 5; alternatively CGI-58) is an evolutionarily conserved protein that acts as a potent activator of Atgl (adipose triglyceride lipase; alternatively, PNPLA2, desnutrin, TTS-2.1) (8). Both proteins are expressed in a variety of tissues, and rare homozygous mutations of either gene in humans produces a...

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Section: E262k Mutation Of Mouse Abhd5 Disrupts Itsmentioning

confidence: 99%

Functional Interactions between Mldp (LSDP5) and Abhd5 in the Control of Intracellular Lipid Accumulation

Granneman

Moore²,

Mottillo

et al. 2009

Journal of Biological Chemistry

124

150

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“…Epidermal 5 caused by CGI-58 deficiency. Thus, we studied the distribution of CGI-58 in the epidermis to obtain clues to clarify the function of CGI-58 and the pathomechanisms of ichthyosis in DCS.…”

Section: Cgi-58 Distribution In the Epidermismentioning

confidence: 99%

“…4 Additional DCS cases with CGI-58 mutations have been reported. [5][6][7] DCS is an autosomal recessively inherited neutral lipid storage disease and is characterized by ichthyosis. 8,9 This entity shows leukocyte lipid vacuoles and involvement of several internal organs, including liver dysfunction, myopathy, cataracts, and a variety of neurological symptoms.…”

mentioning

confidence: 99%

CGI-58 Is an α/β-Hydrolase within Lipid Transporting Lamellar Granules of Differentiated Keratinocytes

Akiyama

Sakai

Takayama

et al. 2008

The American Journal of Pathology

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CGI-58 is the causative molecule underlying DorfmanChanarin syndrome, a neutral lipid storage disease exhibiting apparent clinical features of ichthyosis. CGI-58, associated with triacylglycerol hydrolysis, has an ␣/␤-hydrolase fold and is also known as the ␣/␤-hydrolase domain-containing protein 5. The purpose of this study was to elucidate the function of CGI-58 and the pathogenic mechanisms of ichthyosis in Dorfman-Chanarin syndrome. Using an anti-CGI-58 antibody, we found CGI-58 to be expressed in the upper epidermis, predominantly in the granular layer cells, as well as in neurons and hepatocytes. Immunoelectron microscopy revealed that CGI-58 was also localized to the lamellar granules (LGs), which are lipid transport and secretion granules found in keratinocytes. CGI-58 expression was markedly reduced in the epidermis of patients with harlequin ichthyosis, demonstrating defective LG formation. In cultured keratinocytes, CGI-58 expression was mildly up-regulated under high Ca 2؉ conditions and markedly up-regulated in three-dimensional, organotypic cultures. In the developing human epidermis, CGI-58 immunostaining was observed at an estimated gestational age of 49 days, and CGI-58 mRNA expression was up-regulated concomitantly with both epidermal stratification and keratinocyte differentiation. CGI-58 knockdown reduced expression of keratinocyte differentiation/keratinization markers in cultured human keratinocytes. Our results indicate that CGI-58 is expressed and packaged into LGs during keratinization and likely plays crucial role(s) in keratinocyte differentiation and LG lipid metabolism, contributing to skin lipid barrier formation. (Am J Pathol

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“…Several studies have since confirmed that multiple loss-of-function mutations in CGI-58 are causative of CDS (28)(29)(30)(31). However, CGI-58's role in cellular TG metabolism has yet to be completely elucidated.…”

mentioning

confidence: 99%

“…Further studies have demonstrated that CGI-58 facilitates lipolysis by acting as a coactivator for adipose triglyceride lipase (ATGL) in adipocytes (34,35). However, these studies left several questions unresolved regarding the role of CGI-58 in TG hydrolysis in tissues that express undetectable levels of ATGL (e.g., liver) and whether CGI-58 plays a quantitatively important role in adipose tissue lipolysis, because CDS patients display normal adiposity (27)(28)(29)(30)(31). Importantly, CGI-58 is abundantly expressed in mouse liver (33,34), yet its role in hepatocyte TG metabolism remains obscure.…”

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confidence: 99%

CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells

Brown

Chung

Das

et al. 2007

Journal of Lipid Research

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Comparative Gene Identification-58 (CGI-58) is a member of the a/b-hydrolase family of proteins. Mutations in the human CGI-58 gene are associated with ChanarinDorfman syndrome, a rare autosomal recessive genetic disease in which excessive triglyceride (TG) accumulation occurs in multiple tissues. In this study, we investigated the role of CGI-58 in cellular lipid metabolism in several cell models and discovered a role for CGI-58 in promoting the packaging of cytoplasmic TG into secreted lipoprotein particles in hepatoma cells. Using both gain-of-function and loss-of-function approaches, we demonstrate that CGI-58 facilitates the depletion of cellular TG stores without altering cellular cholesterol or phospholipid accumulation. This depletion of cellular TG is attributable solely to augmented hydrolysis, whereas TG synthesis was not affected by CGI-58. Furthermore, CGI-58-mediated TG hydrolysis can be completely inhibited by the known lipase inhibitors diethylumbelliferyl phosphate and diethyl-p-nitrophenyl phosphate, but not by p-chloro-mercuribenzoate. Intriguingly, CGI-58-driven TG hydrolysis was coupled to increases in both fatty acid oxidation and secretion of TG. Collectively, this study reveals a role for CGI-58 in coupling lipolytic degradation of cytoplasmic TG to oxidation and packaging into TG-rich lipoproteins for secretion in hepatoma cells. The ability to store excess energy in the form of triglyceride (TG) is a critical defense mechanism to help organisms survive extended periods of fuel deprivation. Therefore, elegant systems have evolved to facilitate the storage of excess energy into adipose tissue in the form of TG-rich lipid droplets (LDs) or "adiposomes" (1). Although adipocytes have the unique ability to store large amounts of cytoplasmic TG, almost all tissues can synthesize and store TG in smaller cytoplasmic LDs under normal and pathologic conditions (2-4). The metabolic fate of TG in cytoplasmic LDs differs among cell types (3,(5)(6)(7)(8). Hepatocytes in the liver and enterocytes in the intestine are lipoprotein-producing cells, having the unique ability to efficiently package lipid cargo into apolipoprotein B (apoB)-containing lipoproteins that ultimately deliver these lipids to all peripheral tissues. This assembly of apoB-containing lipoproteins is widely accepted as a twostep process (7,8). The first step involves the cotranslational transfer of a small amount of phospholipids (PLs) and TGs to apoB by the actions of microsomal triglyceride transfer protein (MTP). This step results in a small dense precursor particle (?25 nm) residing within the endoplasmic reticulum (ER) lumen. The more elusive second step involves the bulk addition of TG to these precursor particles to form large (30-80 nm) secretion-competent VLDLs. This second step expansion occurs through an obscure process involving 1) the lipolysis of cytoplasmic LD-associated TG, 2) the movement of liberated acylglycerols toward the ER, and 3) the reesterification of acylglycerols to form a large lumenal TG-rich dro...

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CGI‐58/ABHD5 gene is mutated in Dorfman–Chanarin syndrome

Cited by 16 publications

References 9 publications

Functional Interactions between Mldp (LSDP5) and Abhd5 in the Control of Intracellular Lipid Accumulation

Functional Interactions between Mldp (LSDP5) and Abhd5 in the Control of Intracellular Lipid Accumulation

CGI-58 Is an α/β-Hydrolase within Lipid Transporting Lamellar Granules of Differentiated Keratinocytes

CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells

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