The Minimal Domain of Adipose Triglyceride Lipase (ATGL) Ranges until Leucine 254 and Can Be Activated and Inhibited by CGI-58 and G0S2, Respectively

Cornaciu, Irina; Boeszoermenyi, Andras; Lindermuth, Hanna; Nagy, Harald M.; Cerk, Ines K.; Ebner, Christian; Salzburger, Barbara; Gruber, Astrid; Schweiger, Martina; Zechner, Rudolf; Lass, Achim; Zimmermann, R.; Oberer, Monika

doi:10.1371/journal.pone.0026349

Cited by 76 publications

(108 citation statements)

References 36 publications

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“…The C-terminal domain contains a hydrophobic region, which is essential for LD binding. 13,25 PNPLA2 catalyzes the initial step in the breakdown of intracellular TGs 24 and, as expected; PNPLA2-defective patients showed impaired degradation of cytoplasmic TGs. Experimental knockout of PNPLA2 in mice leads to cytoplasmic accumulation of TGs in multiple tissues.…”

Section: Discussionsupporting

confidence: 75%

Symptomatic lipid storage in carriers for the PNPLA2 gene

et al. 2012

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Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis.

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Section: Discussionsupporting

confidence: 75%

Symptomatic lipid storage in carriers for the PNPLA2 gene

et al. 2012

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“…Although we found the shortest domain with PLA 2 activity to be Met 1 -Ile 202 (PEDF-R4⌬203-232) (Fig. 4), the reported minimum domain for triglyceride lipase activity is slighter longer (Met 1 -Leu 254 ) (46). Differences in substrate recognition (phospholipids versus triglycerides) and/or in recombinant protein expression and purification optimization (i.e.…”

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confidence: 79%

“…Nonetheless, our data clearly demonstrate that the C-terminal half of PEDF-R is dispensable for phospholipid substrate accessibility and/or PLA 2 activity. It has also been reported that the triglyceride lipase activity can be activated or inhibited by CGI-58 or G0S2, respectively (46,49,50), and that PEDF-R binds to these two regulator proteins with a yet unknown binding site (46,51). It remains to be determined if these proteins can compete with PEDF for the binding to PEDF-R.…”

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confidence: 99%

Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R)

Subramanian

Locatelli-Hoops

Kenealey

et al. 2013

Journal of Biological Chemistry

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Background: PEDF has neurotrophic activity and interacts with PEDF-R, a membrane-linked lipase. Results: A PEDF-binding region of PEDF-R is required for PEDF-R enzymatic stimulation, and peptides derived from this region block PEDF⅐PEDF-R-mediated retinal survival activities. Conclusion: A ligand binding domain is identified in PEDF-R, a critical receptor for the survival activity of PEDF. Significance: The findings provide mechanistic insight into the survival activity of PEDF.

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“…The sequence motif containing Thr 372 does not resemble a canonical target for any known kinase. The hydrophobic region is a putative lipid-binding region that has been well known for its role in targeting ATGL to LDs (6,17,23). ATGL mutations have been identified in humans with neutral lipid storage disease characterized by excessive TG deposition in nonadipose tissues and myopathy (8,22).…”

Section: Thrmentioning

confidence: 99%

“…␤-Adrenergic stimulation leads to phosphorylation of perilipin 1 by protein kinase A (PKA) and subsequent translocation of ATGL and HSL to the LD surface (3-5, 7, 24, 26), thereby stimulating lipolysis. Reportedly, the NH 2 -terminal region of ATGL, which contains the proposed catalytic dyad Ser 47 and Asp 166 , is critical for catalytic activity, whereas the COOHterminal region of ATGL controls LD localization (6,22). Although ATGL activation at the LD surface by comparative gene identification-58 (CGI-58) was well studied (9, 10), the exact mechanisms underlying the exclusion of ATGL from LDs in the basal state have remained unclear.…”

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confidence: 99%

Identification of a novel phosphorylation site in adipose triglyceride lipase as a regulator of lipid droplet localization

Xie

Langlais

Zhang

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Xie X, Langlais P, Zhang X, Heckmann BL, Saarinen AM, Mandarino LJ, Liu J. Identification of a novel phosphorylation site in adipose triglyceride lipase as a regulator of lipid droplet localization. Am J Physiol Endocrinol Metab 306: E1449 -E1459, 2014. First published May 6, 2014; doi:10.1152/ajpendo.00663.2013.-Adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triacylglycerol (TG) hydrolysis, has long been known to be a phosphoprotein. However, the potential phosphorylation events that are involved in the regulation of ATGL function remain incompletely defined. Here, using a combinatorial proteomics approach, we obtained evidence that at least eight different sites of ATGL can be phosphorylated in adipocytes. Among them, Thr 372 resides within the hydrophobic region known to mediate lipid droplet (LD) targeting. Although it had no impact on the TG hydrolase activity, substitution of phosphorylation-mimic Asp for Thr 372 eliminated LD localization and LD-degrading capacity of ATGL expressed in HeLa cells. In contrast, mutation of Thr 372 to Ala gave a protein that bound LDs and functioned the same as the wild-type protein. In nonstimulated adipocytes, the Asp mutation led to decreased LD association and basal lipolytic activity of ATGL, whereas the Ala mutation produced opposite effects. Moreover, the LD translocation of ATGL upon ␤-adrenergic stimulation was also compromised by the Asp mutation. In accord with these findings, the Ala mutation promoted and the Asp mutation attenuated the capacity of ATGL to mediate lipolysis in adipocytes under both basal and stimulated conditions. Collectively, these studies identified Thr 372 as a novel phosphorylation site that may play a critical role in determining subcellular distribution as well as lipolytic action of ATGL. lipolysis; triglyceride; lipid metabolism; adipose triglyceride lipase; phosphorylation; lipid droplet LIPID DROPLETS (LDs) are intracellular depots for neutral lipids such as triacylglycerols (TGs) and cholesteryl esters and play essential roles in providing energy substrate during times of nutrient deprivation or enhanced energy demand (13). A key process in energy catabolism is the lipolytic breakdown of TGs in adipose tissue and the release of free fatty acids (FFAs) and glycerol. To date, three enzymes, namely adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL), have been found to be critical for lipolysis at different steps in adipocytes (12,16,27). ATGL initiates TG breakdown, resulting in the release of one fatty acid (FA) and diacylglycerol (DG). HSL hydrolyzes DG to FA and monoacylglycerol (MG), the latter of which then is converted to glycerol and FA by MGL.In adipocytes, catecholamines acting on ␤-adrenergic receptors and insulin functioning through insulin receptor represent the most potent stimulatory and inhibitory hormones, respectively, in lipolysis (12,16,27). In the basal state, a majority of ATGL and HSL proteins reside in the cytoplasm of adipocytes. ␤-Adrenergic stimul...

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The Minimal Domain of Adipose Triglyceride Lipase (ATGL) Ranges until Leucine 254 and Can Be Activated and Inhibited by CGI-58 and G0S2, Respectively

Cited by 76 publications

References 36 publications

Symptomatic lipid storage in carriers for the PNPLA2 gene

Symptomatic lipid storage in carriers for the PNPLA2 gene

Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R)

Identification of a novel phosphorylation site in adipose triglyceride lipase as a regulator of lipid droplet localization

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