Independence of triacylglycerol‐containing compartments in cultured fibroblasts from Wolman disease and multisystemic lipid storage myopathy

Salvayre, Robert; Nègre, Anne; Radom, Jean; Douste‐Blazy, Louis

doi:10.1016/0014-5793(89)80679-9

Cited by 19 publications

(21 citation statements)

References 24 publications

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“…The accrual of neutral lipids was shown not to be caused by a defect in mitochondrial fatty acid (FA) uptake or defective ␤-oxidation (42,60). Also, enzymatic activities of lipases, carboxyesterases (25,48,59,60), and enzymes for the glycerolipid synthesis (24,59) were normal in most studies. Hilaire et al (22), however, observed an impaired degradation of TG containing long-chain FA in NLSD cells, suggesting a defect in long-chain TG hydrolase activity.…”

Section: Mutations In Cgi-58 Cause Nlsd With Ichthyosismentioning

confidence: 93%

Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2orCGI-58/ABHD5

Schweiger

Lass²,

Zimmermann³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

253

268

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Neutral lipid storage disease (NLSD) is a group of autosomal recessive disorders characterized by the excessive accumulation of neutral lipids in multiple tissues. Recently, two genes, adipose triglyceride lipase (ATGL/PNPLA2) and comparative gene identification-58 (CGI-58/ABHD5), have been shown to cause NLSD. ATGL specifically hydrolyzes the first fatty acid from triacylglycerols (TG) and CGI-58/ ABHD5 stimulates ATGL activity by a currently unknown mechanism. Mutations in both the ATGL and the CGI-58 genes are associated with systemic TG accumulation, yet the resulting clinical manifestations are not identical. Patients with defective ATGL function suffer from more severe myopathy (NLSDM) than patients with defective CGI-58 function. On the other hand, CGI-58 mutations are always associated with ichthyosis (NLSDI), which was not observed in patients with defective ATGL function. These observations indicate an ATGL-independent function of CGI-58. This review summarizes recent findings with the goal of relating structural variants of ATGL and CGI-58 to functional consequences in lipid metabolism.

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Section: Mutations In Cgi-58 Cause Nlsd With Ichthyosismentioning

confidence: 93%

Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2orCGI-58/ABHD5

Schweiger

Lass²,

Zimmermann³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

253

268

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“…Several elegant studies done using fibroblasts derived from CDS patients demonstrated that the excess TG accumulation in these cells did not result from augmented fatty acid uptake or TG synthesis rates (19,20). Instead, fibroblasts from CDS patients seem to lack the ability to hydrolyze stored TG, even though cellular lipase and carboxylesterase activities are normal (20)(21)(22). As a result of this paradoxical finding, it has been speculated that TG lipases in these cells may be missing some critical cofactor, be mislocalized, or be unable to gain access to the LD surface (23,24).…”

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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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“…In human fibroblasts, triacylglycerols are degraded in two separate and independent subcellular (lysosomal and cytoplasmic non-lysosomal) compartments (1). In the lysosomal compartment, triacylglycerols and cholesteryl esters of low density lipoprotein and very low density lipoprotein taken up by cells are degraded by the acid lysosomal lipase (2,3), which is genetically deficient in Wolman disease (4).…”

mentioning

confidence: 99%

“…In the lysosomal compartment, triacylglycerols and cholesteryl esters of low density lipoprotein and very low density lipoprotein taken up by cells are degraded by the acid lysosomal lipase (2,3), which is genetically deficient in Wolman disease (4). In the cytoplasmic compartment of fibroblasts, triacylglycerols are degraded by a lipase system (yet poorly characterized) different from the other known cellular (hormone-sensitive lipase) or secretory lipases (1,5) and different from the cholesteryl ester degradation pathway (6). As shown by using radiolabeled oleic acid or pyrene-containing fluorescent fatty acids, this degradative pathway of cytoplasmic triacylglycerols is deficient in the neutral lipid storage disease (NLSD) 1 (1, 5, 7-10), a rare inherited metabolic disease generally characterized by the association of muscular weakness, ichthyosis, and multisystemic triacylglycerol storage (11,12).…”

mentioning

confidence: 99%

The Turnover of Cytoplasmic Triacylglycerols in Human Fibroblasts Involves Two Separate Acyl Chain Length-dependent Degradation Pathways

Hilaire¹,

Salvayre

Thiers

et al. 1995

Journal of Biological Chemistry

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Cultured fibroblasts from patients affected with the genetic metabolic disorder named neutral lipid storage disease (NLSD) exhibit a dramatic accumulation of cytoplasmic triacylglycerols (Radom, J., Salvayre, R., Nè gre, A., Maret, A., and Douste-Blazy, L. (1987) Eur. J. Biochem. 164, 703-708). We compared here the metabolism of radiolabeled short-, medium-and long-chain fatty acids in these cells. Short/medium-chain fatty acids (C4 -C10) were incorporated into polar lipids (60 -80%) and triacylglycerols (20 -40%) at a lower rate (5-10 times lower) than long-chain fatty acids. Pulse-chase experiments allowed to evaluate the degradation rate of cytoplasmic triacylglycerols in normal and NLSD fibroblasts and to discriminate between two catabolic pathways of cytoplasmic triacylglycerols. Short/medium-chain (C4 -C10) triacylglycerols were degraded at a normal rate in NLSD fibroblasts, whereas long-chain (C12 and longer) triacylglycerols remained undegraded. These data are confirmed by mass analysis. The use of diethylparanitrophenyl phosphate (E600) and parachloromercuribenzoate (PCMB) inhibitors allows to discriminate between the two triacylglycerol degradation pathways. E600 inhibited selectively the in situ degradation of short/medium-chain triacylglycerols without inhibition of the degradation of long-chain triacylglycerols, whereas PCMB inhibited selectively the in situ hydrolysis of long-chain triacylglycerols without affecting the degradation of long-chain triacylglycerols. This was correlated with the in vitro properties of cellular triacylglycerol-hydrolyzing enzymes characterized by their susbtrate specificity and their susceptibility to inhibitors; the neutral lipase specific to long-chain triacylglycerols is inhibited by PCMB, but not by E600, in contrast to short/medium-chain lipase, which is inhibited by E600 but not by PCMB. The data of in vitro and in situ experiments suggest the existence in fibroblasts of two separate acyl chain length-dependent pathways involved in the degradation of cytoplasmic triacylglycerols, one mediated by a neutral long-chain lipase and another one mediated by a short/medium-chain lipase.

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Independence of triacylglycerol‐containing compartments in cultured fibroblasts from Wolman disease and multisystemic lipid storage myopathy

Cited by 19 publications

References 24 publications

Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2orCGI-58/ABHD5

Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2orCGI-58/ABHD5

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

The Turnover of Cytoplasmic Triacylglycerols in Human Fibroblasts Involves Two Separate Acyl Chain Length-dependent Degradation Pathways

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