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ABSTRACT: Lipid droplets (LDs) represent specialized cell organelles for the storage of energy rich lipids. Although lipid storage is a conserved feature of all cells and organisms, only little is known about fundamental aspects of the cell biology of LDs, including their biogenesis, structural assembly and subcellular positioning, and the regulation of organismic energy homeostasis.We identified a novel LD-associated protein family, represented by the Drosophila protein CG9186 and its murine homolog MGI:1916082. In the absence of LDs, both proteins localize at the endoplasmic reticulum (ER). Upon lipid storage induction, they translocate to LDs using an evolutionary conserved targeting mechanism that acts via a 60 amino acids targeting motif in the center of the CG9186 protein. Overexpression of CG9186 and MGI:1916082 causes clustering of LDs in both tissue culture and salivary gland cells, whereas the RNAi knockdown results in a reduction of LDs. Organismal RNAi knock-down of CG9186 results in a reduction of the lipid storage levels of the fly. The results indicate that we identified the first members of a novel and evolutionary conserved family of lipid storage regulators, which are also required to properly position LDs within cells.
Journal of Cell Science 03/2013; · 6.11 Impact Factor
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Nina M Pollak,
Martina Schweiger,
Doris Jaeger,
Dagmar Kolb,
Manju Kumari,
Renate Schreiber,
Stephanie Kolleritsch,
Philipp Markolin,
Gernot F Grabner, Christoph Heier,
Kathrin A Zierler,
Thomas Ruelicke,
Robert Zimmermann,
Achim Lass,
Rudolf Zechner,
Guenter Haemmerle
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ABSTRACT: Cardiac triacylglycerol (TG) catabolism critically depends on the TG hydrolytic activity of adipose triglyceride lipase (ATGL). Perilipin 5 (Plin5) is expressed in cardiac muscle (CM) and has been shown to interact with ATGL and its co-activator comparative gene identification-58 (CGI-58). Furthermore, ectopic Plin5 expression increases cellular TG content and Plin5-deficient mice exhibit reduced cardiac TG levels. In this study we show that mice with CM-specific overexpression of Plin5 (CM-Plin5) massively accumulate TG in CM, which is accompanied by moderately reduced fatty acid (FA) oxidizing gene expression levels. Cardiac lipid droplet (LD) preparations from CM of CM-Plin5 mice showed reduced ATGL- and hormone-sensitive lipase-mediated TG mobilization implying that Plin5 overexpression restricts cardiac lipolysis via the formation of a lipolytic barrier. To test this hypothesis, we analyzed TG hydrolytic activities in preparations of Plin5-, ATGL- and CGI-58-transfected cells. In vitro ATGL-mediated TG hydrolysis of an artificial micellar TG substrate was not inhibited by the presence of Plin5, whereas Plin5-coated LDs were resistant towards ATGL-mediated TG catabolism. These findings strongly suggest that Plin5 functions as a lipolytic barrier to protect the cardiac TG pool from uncontrolled TG mobilization and the excessive release of free FAs.
The Journal of Lipid Research 01/2013; · 5.56 Impact Factor
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Nina M. Pollak,
Martina Schweiger,
Doris Jaeger,
Dagmar Kolb,
Manju Kumari,
Renate Schreiber,
Stephanie Kolleritsch,
Philipp Markolin,
Gernot F. Grabner, Christoph Heier,
Kathrin A. Zierler,
Thomas Rülicke,
Robert Zimmermann,
Achim Lass,
Rudolf Zechner,
and Guenter Haemmerle
The Journal of Lipid Research 01/2012; · 5.56 Impact Factor
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Ulrike Taschler,
Franz P. W. Radner, Christoph Heier,
Renate Schreiber,
Martina Schweiger,
Gabriele Schoiswohl,
Karina Preiss-Landl,
Doris Jaeger,
Birgit Reiter,
Harald C. Koefeler,
Jacek Wojciechowski,
Christian Theussl,
Josef M. Penninger,
Achim Lass,
Guenter Haemmerle,
Rudolf Zechner,
Robert Zimmermann
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ABSTRACT: Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols
(MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades
2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects
energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize
the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant
increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated
by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well
as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice
exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the
CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly,
however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in
comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency
impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like
effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.
Journal of Biological Chemistry 05/2011; 286(20):17467-17477. · 4.77 Impact Factor
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Ulrike Taschler,
Franz P W Radner, Christoph Heier,
Renate Schreiber,
Martina Schweiger,
Gabriele Schoiswohl,
Karina Preiss-Landl,
Doris Jaeger,
Birgit Reiter,
Harald C Koefeler,
Jacek Wojciechowski,
Christian Theussl,
Josef M Penninger,
Achim Lass,
Guenter Haemmerle,
Rudolf Zechner,
Robert Zimmermann
[show abstract]
[hide abstract]
ABSTRACT: Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.
Journal of Biological Chemistry 03/2011; 286(20):17467-77. · 4.77 Impact Factor
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ABSTRACT: Monoacylglycerols (MAGs) are short-lived intermediates of glycerolipid metabolism. Specific molecular species, such as 2-arachidonoylglycerol, which is a potent activator of cannabinoid receptors, may also function as lipid signaling molecules. In mammals, enzymes hydrolyzing MAG to glycerol and fatty acids, resembling the final step in lipolysis, or esterifying MAG to diacylglycerol, are well known; however, despite the high level of conservation of lipolysis, the corresponding activities in yeast have not been characterized yet. Here we provide evidence that the protein Yju3p functions as a potent MAG hydrolase in yeast. Cellular MAG hydrolase activity was decreased by more than 90% in extracts of Yju3p-deficient cells, indicating that Yju3p accounts for the vast majority of this activity in yeast. Loss of this activity was restored by heterologous expression of murine monoglyceride lipase (MGL). Since yju3Delta mutants accumulated MAG in vivo only at very low concentrations, we considered the possibility that MAGs are re-esterified into DAG by acyltransferases. Indeed, cellular MAG levels were further increased in mutant cells lacking Yju3p and Dga1p or Lro1p acyltransferase activities. In conclusion, our studies suggest that catabolic and anabolic reactions affect cellular MAG levels. Yju3p is the functional orthologue of mammalian MGL and is required for efficient degradation of MAG in yeast.
Biochimica et Biophysica Acta 09/2010; 1801(9):1063-71. · 4.66 Impact Factor
