The Experts below are selected from a list of 3441 Experts worldwide ranked by ideXlab platform

Martina Schweiger - One of the best experts on this subject based on the ideXlab platform.

  • pharmacological inhibition of Adipose Triglyceride Lipase corrects high fat diet induced insulin resistance and hepatosteatosis in mice
    Nature Communications, 2017
    Co-Authors: Martina Schweiger, Renate Schreiber, Petra Kotzbeck, Thomas O Eichmann, Matthias Romauch, Gernot F Grabner, Sabrina Hutter, Pia Benedikt, Sohsuke Yamada, Oskar Knittelfelder
    Abstract:

    Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing Adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of Adipose Triglyceride Lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces Adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders. The enzyme Atgl participates in the breakdown of lipids in Adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.

  • a peptide derived from g0 g1 switch gene 2 acts as noncompetitive inhibitor of Adipose Triglyceride Lipase
    Journal of Biological Chemistry, 2014
    Co-Authors: Ines K Cerk, Martina Schweiger, Achim Lass, Irina Cornaciu, Christoph Heier, Matthias Romauch, Barbara Salzburger, Andras Boeszoermenyi, Christoph Pillip, Robert Zimmermann
    Abstract:

    The protein G0/G1 switch gene 2 (G0S2) is a small basic protein that functions as an endogenous inhibitor of Adipose Triglyceride Lipase (ATGL), a key enzyme in intracellular lipolysis. In this study, we identified a short sequence covering residues Lys-20 to Ala-52 in G0S2 that is still fully capable of inhibiting mouse and human ATGL. We found that a synthetic peptide corresponding to this region inhibits ATGL in a noncompetitive manner in the nanomolar range. This peptide is highly selective for ATGL and does not inhibit other Lipases, including hormone-sensitive Lipase, monoacylglycerol Lipase, lipoprotein Lipase, and patatin domain-containing phosphoLipases 6 and 7. Because increased lipolysis is linked to the development of metabolic disorders, the inhibition of ATGL by G0S2-derived peptides may represent a novel therapeutic tool to modulate lipolysis.

  • The hepatitis C virus core protein inhibits Adipose Triglyceride Lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets.
    The Journal of biological chemistry, 2014
    Co-Authors: Gregory Camus, Martina Schweiger, Robert V Farese, Eva Herker, Charles A. Harris, Andrew S. Kondratowicz, Chia-lin Tsou, Kithsiri Herath, Stephen F. Previs, Thomas P. Roddy
    Abstract:

    Abstract Liver steatosis is a common health problem associated with hepatitis C virus (HCV) and an important risk factor for the development of liver fibrosis and cancer. Steatosis is caused by Triglycerides (TG) accumulating in lipid droplets (LDs), cellular organelles composed of neutral lipids surrounded by a monolayer of phospholipids. The HCV nucleocapsid core localizes to the surface of LDs and induces steatosis in cultured cells and mouse livers by decreasing intracellular TG degradation (lipolysis). Here, we report that core at the surface of LDs interferes with the activity of Adipose Triglyceride Lipase (ATGL), the key lipolytic enzyme in the first step of TG breakdown. Expressing core in livers or mouse embryonic fibroblasts of ATGL-/- mice no longer decreases TG degradation as observed in LDs from wild-type mice, supporting the model that core reduces lipolysis by engaging ATGL. Core must localize at LDs to inhibit lipolysis, as ex vivo TG hydrolysis is impaired in purified LDs coated with core, but not when free core is added to LDs. Coimmunoprecipitation experiments revealed that core does not directly interact with the ATGL complex, but unexpectedly, increased the interaction between ATGL and its activator CGI-58, as well as the recruitment of both proteins to LDs. These data link the anti-lipolytic activity of the HCV core protein with altered ATGL binding to CGI-58 and the enhanced association of both proteins with LDs.

  • endothelial dysfunction in Adipose Triglyceride Lipase deficiency
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Astrid Schrammel, Martina Schweiger, Guenter Haemmerle, Marion Mussbacher, Gerald Wolkart, Heike Stessel, Karoline Pail, Sarah Winkler, Wael Al Zoughbi, Gerald Hofler
    Abstract:

    Systemic knockout of Adipose Triglyceride Lipase (ATGL), the pivotal enzyme of Triglyceride lipolysis, results in a murine phenotype that is characterized by progredient cardiac steatosis and severe heart failure. Since cardiac and vascular dysfunction have been closely related in numerous studies we investigated endothelium-dependent and -independent vessel function of ATGL knockout mice. Aortic relaxation studies and Langendorff perfusion experiments of isolated hearts showed that ATGL knockout mice suffer from pronounced micro- and macrovascular endothelial dysfunction. Experiments with agonists directly targeting vascular smooth muscle cells revealed the functional integrity of the smooth muscle cell layer. Loss of vascular reactivity was restored ~50% upon treatment of ATGL knockout mice with the PPARα agonist Wy14,643, indicating that this phenomenon is partly a consequence of impaired cardiac contractility. Biochemical analysis revealed that aortic endothelial NO synthase expression and activity were significantly reduced in ATGL deficiency. Enzyme activity was fully restored in ATGL mice treated with the PPARα agonist. Biochemical analysis of perivascular Adipose tissue demonstrated that ATGL knockout mice suffer from perivascular inflammatory oxidative stress which occurs independent of cardiac dysfunction and might contribute to vascular defects. Our results reveal a hitherto unrecognized link between disturbed lipid metabolism, obesity and cardiovascular disease.

  • fat specific protein 27 fsp27 interacts with Adipose Triglyceride Lipase atgl to regulate lipolysis and insulin sensitivity in human adipocytes
    Journal of Biological Chemistry, 2014
    Co-Authors: Tan Hooi Min Grahn, Martina Schweiger, Achim Lass, Vishva M. Sharma, Rajween Kaur, Cynthia M Smas, Rudolf Zechner, Vishwajeet Puri
    Abstract:

    Abstract In adipocytes, lipolysis is a highly regulated process involving hormonal signals, lipid droplet-associated proteins, and Lipases. The discovery of new lipid droplet-associated proteins added complexity to the current model of lipolysis. In this study, we used cultured human adipocytes to demonstrate that fat-specific protein 27 (FSP27), an abundantly expressed protein in adipocytes, regulates both basal and stimulated lipolysis by interacting with Adipose Triglyceride Lipase (ATGL, also called desnutrin or PNPLA2). We identified a core domain of FSP27, amino acids 120–220, that interacts with ATGL to inhibit its lipolytic function and promote Triglyceride storage. We also defined the role of FSP27 in free fatty acid-induced insulin resistance in adipocytes. FSP27 depletion in human adipocytes increased lipolysis and inhibited insulin signaling by decreasing AKT phosphorylation. However, reducing lipolysis by either depletion of ATGL or expression of exogenous full-length FSP27 or amino acids 120–220 protected human adipocytes against the adverse effects of free fatty acids on insulin signaling. In embryonic fibroblasts derived from ATGL KO mice, exogenous free fatty acids did not affect insulin sensitivity. Our results demonstrate a crucial role for FSP27-ATGL interactions in regulating lipolysis, Triglyceride accumulation, and insulin signaling in human adipocytes.

Rudolf Zechner - One of the best experts on this subject based on the ideXlab platform.

  • Micro RNA-124a Regulates Lipolysis via Adipose Triglyceride Lipase and Comparative Gene Identification 58
    International Journal of Molecular Sciences, 2015
    Co-Authors: Suman Das, Silvia Schauer, Gerald Hoefler, Rudolf Zechner, Elke Stadelmeyer, Anna Schwarz, Heimo Strohmaier, Thiery Claudel, Paul Vesely
    Abstract:

    Lipolysis is the biochemical pathway responsible for the catabolism of cellular triacylglycerol (TG). Lipolytic TG breakdown is a central metabolic process leading to the generation of free fatty acids (FA) and glycerol, thereby regulating lipid, as well as energy homeostasis. The precise tuning of lipolysis is imperative to prevent lipotoxicity, obesity, diabetes and other related metabolic disorders. Here, we present our finding that miR-124a attenuates RNA and protein expression of the major TG hydrolase, Adipose Triglyceride Lipase (ATGL/PNPLA2) and its co-activator comparative gene identification 58 (CGI-58/ABHD5). Ectopic expression of miR-124a in adipocytes leads to reduced lipolysis and increased cellular TG accumulation. This phenotype, however, can be rescued by overexpression of truncated Atgl lacking its 3'UTR, which harbors the identified miR-124a target site. In addition, we observe a strong negative correlation between miR-124a and Atgl expression in various murine tissues. Moreover, miR-124a regulates the expression of Atgl and Cgi-58 in murine white Adipose tissue during fasting as well as the expression of Atgl in murine liver, during fasting and re-feeding. Together, these results point to an instrumental role of miR-124a in the regulation of TG catabolism. Therefore, we suggest that miR-124a may be involved in the regulation of several cellular and organismal metabolic parameters, including lipid storage and plasma FA concentration

  • fat specific protein 27 fsp27 interacts with Adipose Triglyceride Lipase atgl to regulate lipolysis and insulin sensitivity in human adipocytes
    Journal of Biological Chemistry, 2014
    Co-Authors: Tan Hooi Min Grahn, Martina Schweiger, Achim Lass, Vishva M. Sharma, Rajween Kaur, Cynthia M Smas, Rudolf Zechner, Vishwajeet Puri
    Abstract:

    Abstract In adipocytes, lipolysis is a highly regulated process involving hormonal signals, lipid droplet-associated proteins, and Lipases. The discovery of new lipid droplet-associated proteins added complexity to the current model of lipolysis. In this study, we used cultured human adipocytes to demonstrate that fat-specific protein 27 (FSP27), an abundantly expressed protein in adipocytes, regulates both basal and stimulated lipolysis by interacting with Adipose Triglyceride Lipase (ATGL, also called desnutrin or PNPLA2). We identified a core domain of FSP27, amino acids 120–220, that interacts with ATGL to inhibit its lipolytic function and promote Triglyceride storage. We also defined the role of FSP27 in free fatty acid-induced insulin resistance in adipocytes. FSP27 depletion in human adipocytes increased lipolysis and inhibited insulin signaling by decreasing AKT phosphorylation. However, reducing lipolysis by either depletion of ATGL or expression of exogenous full-length FSP27 or amino acids 120–220 protected human adipocytes against the adverse effects of free fatty acids on insulin signaling. In embryonic fibroblasts derived from ATGL KO mice, exogenous free fatty acids did not affect insulin sensitivity. Our results demonstrate a crucial role for FSP27-ATGL interactions in regulating lipolysis, Triglyceride accumulation, and insulin signaling in human adipocytes.

  • Adipose Triglyceride Lipase activity is inhibited by long chain acyl coenzyme a
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Harald M Nagy, Achim Lass, Margret Paar, Guenter Haemmerle, Rudolf Zechner, Tarek Moustafa, Monika Oberer, Christoph Heier, Peter Hofer, Robert Zimmermann
    Abstract:

    Adipose Triglyceride Lipase (ATGL) is required for efficient mobilization of Triglyceride (TG) stores in Adipose tissue and non-Adipose tissues. Therefore, ATGL strongly determines the availability of fatty acids for metabolic reactions. ATGL activity is regulated by a complex network of lipolytic and anti-lipolytic hormones. These signals control enzyme expression and the interaction of ATGL with the regulatory proteins CGI-58 and G0S2. Up to date, it was unknown whether ATGL activity is also controlled by lipid intermediates generated during lipolysis. Here we show that ATGL activity is inhibited by long-chain acyl-CoAs in a non-competitive manner, similar as previously shown for hormone-sensitive Lipase (HSL), the rate-limiting enzyme for diglyceride breakdown in Adipose tissue. ATGL activity is only marginally inhibited by medium-chain acyl-CoAs, diglycerides, monoglycerides, and free fatty acids. Immunoprecipitation assays revealed that acyl-CoAs do not disrupt the protein–protein interaction of ATGL and its co-activator CGI-58. Furthermore, inhibition of ATGL is independent of the presence of CGI-58 and occurs directly at the N-terminal patatin-like phosphoLipase domain of the enzyme. In conclusion, our results suggest that inhibition of the major lipolytic enzymes ATGL and HSL by long-chain acyl-CoAs could represent an effective feedback mechanism controlling lipolysis and protecting cells from lipotoxic concentrations of fatty acids and fatty acid-derived lipid metabolites.

  • Role of Adipose Triglyceride Lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia.
    Hepatology (Baltimore Md.), 2014
    Co-Authors: Pooja Jha, Suman K. Das, Robert Zimmermann, Achim Lass, Rudolf Zechner, Thierry Claudel, Anna Baghdasaryan, Michaela Mueller, Emina Halilbasic, Gerald Hoefler
    Abstract:

    Hepatic inflammation is a key feature of progressive liver disease. Alterations of fatty acid (FA) metabolism and signaling may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Moreover, FAs activate peroxisome proliferator-activated receptor α (PPARα) as a key transcriptional regulator of hepatic FA metabolism and inflammation. Since Adipose Triglyceride Lipase (ATGL/PNPLA2) is the key enzyme for intracellular hydrolysis of stored Triglycerides and determines FA signaling through PPARα, we explored the role of ATGL in hepatic inflammation in mouse models of NASH and endotoxemia. Mice lacking ATGL or hormone-sensitive Lipase (HSL) were challenged with a methionine-choline-deficient (MCD) diet as a nutritional model of NASH or lipopolysaccharide (LPS) as a model of acute hepatic inflammation. We further tested whether a PPARα agonist (fenofibrate) treatment improves the hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice. MCD-fed ATGL-KO mice, although partially protected from peripheral lipolysis, showed exacerbated hepatic steatosis and inflammation. Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic inflammation, increased mortality, and torpor, findings which were attributed to impaired PPARα DNA binding activity due to reduced FABP1 protein levels, resulting in impaired nuclear FA import. Notably, liganding PPARα through fenofibrate attenuated hepatic inflammation in both MCD-fed and LPS-treated ATGL-KO mice. In contrast, mice lacking HSL had a phenotype similar to the WT mice on MCD and LPS challenge. Conclusion: These findings unravel a novel protective role of ATGL against hepatic inflammation which could have important implications for metabolic and inflammatory liver diseases. (Hepatology 2014;59:858–869)

  • early structural and metabolic cardiac remodelling in response to inducible Adipose Triglyceride Lipase ablation
    Cardiovascular Research, 2013
    Co-Authors: Petra C. Kienesberger, Juliane G Bognerstrauss, Thomas Pulinilkunnil, Martin E Young, Guenter Haemmerle, J Nagendran, Hubert Hackl, Rammy Khadour, Emma Heydari, Rudolf Zechner
    Abstract:

    Aims While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as Adipose Triglyceride Lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor α (PPARα) activity and subsequent fatty acid oxidation (FAO). However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARα activity, cardiac function, and metabolism is not known. Methods and results To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (ic Atgl KO). Within 4–6 weeks following ATGL ablation, ic Atgl KO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in ic Atgl KO mice. Analysis of energy metabolism in e x vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression. Conclusions This study shows that acquired cardiomyocyte-specific ATGL deficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARα signalling.

Achim Lass - One of the best experts on this subject based on the ideXlab platform.

  • a peptide derived from g0 g1 switch gene 2 acts as noncompetitive inhibitor of Adipose Triglyceride Lipase
    Journal of Biological Chemistry, 2014
    Co-Authors: Ines K Cerk, Martina Schweiger, Achim Lass, Irina Cornaciu, Christoph Heier, Matthias Romauch, Barbara Salzburger, Andras Boeszoermenyi, Christoph Pillip, Robert Zimmermann
    Abstract:

    The protein G0/G1 switch gene 2 (G0S2) is a small basic protein that functions as an endogenous inhibitor of Adipose Triglyceride Lipase (ATGL), a key enzyme in intracellular lipolysis. In this study, we identified a short sequence covering residues Lys-20 to Ala-52 in G0S2 that is still fully capable of inhibiting mouse and human ATGL. We found that a synthetic peptide corresponding to this region inhibits ATGL in a noncompetitive manner in the nanomolar range. This peptide is highly selective for ATGL and does not inhibit other Lipases, including hormone-sensitive Lipase, monoacylglycerol Lipase, lipoprotein Lipase, and patatin domain-containing phosphoLipases 6 and 7. Because increased lipolysis is linked to the development of metabolic disorders, the inhibition of ATGL by G0S2-derived peptides may represent a novel therapeutic tool to modulate lipolysis.

  • fat specific protein 27 fsp27 interacts with Adipose Triglyceride Lipase atgl to regulate lipolysis and insulin sensitivity in human adipocytes
    Journal of Biological Chemistry, 2014
    Co-Authors: Tan Hooi Min Grahn, Martina Schweiger, Achim Lass, Vishva M. Sharma, Rajween Kaur, Cynthia M Smas, Rudolf Zechner, Vishwajeet Puri
    Abstract:

    Abstract In adipocytes, lipolysis is a highly regulated process involving hormonal signals, lipid droplet-associated proteins, and Lipases. The discovery of new lipid droplet-associated proteins added complexity to the current model of lipolysis. In this study, we used cultured human adipocytes to demonstrate that fat-specific protein 27 (FSP27), an abundantly expressed protein in adipocytes, regulates both basal and stimulated lipolysis by interacting with Adipose Triglyceride Lipase (ATGL, also called desnutrin or PNPLA2). We identified a core domain of FSP27, amino acids 120–220, that interacts with ATGL to inhibit its lipolytic function and promote Triglyceride storage. We also defined the role of FSP27 in free fatty acid-induced insulin resistance in adipocytes. FSP27 depletion in human adipocytes increased lipolysis and inhibited insulin signaling by decreasing AKT phosphorylation. However, reducing lipolysis by either depletion of ATGL or expression of exogenous full-length FSP27 or amino acids 120–220 protected human adipocytes against the adverse effects of free fatty acids on insulin signaling. In embryonic fibroblasts derived from ATGL KO mice, exogenous free fatty acids did not affect insulin sensitivity. Our results demonstrate a crucial role for FSP27-ATGL interactions in regulating lipolysis, Triglyceride accumulation, and insulin signaling in human adipocytes.

  • Adipose Triglyceride Lipase activity is inhibited by long chain acyl coenzyme a
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Harald M Nagy, Achim Lass, Margret Paar, Guenter Haemmerle, Rudolf Zechner, Tarek Moustafa, Monika Oberer, Christoph Heier, Peter Hofer, Robert Zimmermann
    Abstract:

    Adipose Triglyceride Lipase (ATGL) is required for efficient mobilization of Triglyceride (TG) stores in Adipose tissue and non-Adipose tissues. Therefore, ATGL strongly determines the availability of fatty acids for metabolic reactions. ATGL activity is regulated by a complex network of lipolytic and anti-lipolytic hormones. These signals control enzyme expression and the interaction of ATGL with the regulatory proteins CGI-58 and G0S2. Up to date, it was unknown whether ATGL activity is also controlled by lipid intermediates generated during lipolysis. Here we show that ATGL activity is inhibited by long-chain acyl-CoAs in a non-competitive manner, similar as previously shown for hormone-sensitive Lipase (HSL), the rate-limiting enzyme for diglyceride breakdown in Adipose tissue. ATGL activity is only marginally inhibited by medium-chain acyl-CoAs, diglycerides, monoglycerides, and free fatty acids. Immunoprecipitation assays revealed that acyl-CoAs do not disrupt the protein–protein interaction of ATGL and its co-activator CGI-58. Furthermore, inhibition of ATGL is independent of the presence of CGI-58 and occurs directly at the N-terminal patatin-like phosphoLipase domain of the enzyme. In conclusion, our results suggest that inhibition of the major lipolytic enzymes ATGL and HSL by long-chain acyl-CoAs could represent an effective feedback mechanism controlling lipolysis and protecting cells from lipotoxic concentrations of fatty acids and fatty acid-derived lipid metabolites.

  • Role of Adipose Triglyceride Lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia.
    Hepatology (Baltimore Md.), 2014
    Co-Authors: Pooja Jha, Suman K. Das, Robert Zimmermann, Achim Lass, Rudolf Zechner, Thierry Claudel, Anna Baghdasaryan, Michaela Mueller, Emina Halilbasic, Gerald Hoefler
    Abstract:

    Hepatic inflammation is a key feature of progressive liver disease. Alterations of fatty acid (FA) metabolism and signaling may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Moreover, FAs activate peroxisome proliferator-activated receptor α (PPARα) as a key transcriptional regulator of hepatic FA metabolism and inflammation. Since Adipose Triglyceride Lipase (ATGL/PNPLA2) is the key enzyme for intracellular hydrolysis of stored Triglycerides and determines FA signaling through PPARα, we explored the role of ATGL in hepatic inflammation in mouse models of NASH and endotoxemia. Mice lacking ATGL or hormone-sensitive Lipase (HSL) were challenged with a methionine-choline-deficient (MCD) diet as a nutritional model of NASH or lipopolysaccharide (LPS) as a model of acute hepatic inflammation. We further tested whether a PPARα agonist (fenofibrate) treatment improves the hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice. MCD-fed ATGL-KO mice, although partially protected from peripheral lipolysis, showed exacerbated hepatic steatosis and inflammation. Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic inflammation, increased mortality, and torpor, findings which were attributed to impaired PPARα DNA binding activity due to reduced FABP1 protein levels, resulting in impaired nuclear FA import. Notably, liganding PPARα through fenofibrate attenuated hepatic inflammation in both MCD-fed and LPS-treated ATGL-KO mice. In contrast, mice lacking HSL had a phenotype similar to the WT mice on MCD and LPS challenge. Conclusion: These findings unravel a novel protective role of ATGL against hepatic inflammation which could have important implications for metabolic and inflammatory liver diseases. (Hepatology 2014;59:858–869)

  • development of small molecule inhibitors targeting Adipose Triglyceride Lipase
    Nature Chemical Biology, 2013
    Co-Authors: Nicole Mayer, Martina Schweiger, Thomas O Eichmann, Christoph Heier, Matthias Romauch, Gernot F Grabner, Elisabeth Fuchs, Jakov Ivkovic, Irina Mrak, Achim Lass
    Abstract:

    Adipose Triglyceride Lipase (ATGL) is rate limiting in the mobilization of fatty acids from cellular Triglyceride stores. This central role in lipolysis marks ATGL as an interesting pharmacological target as deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Here we report on the development and characterization of a small-molecule inhibitor of ATGL. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo.

Robert Zimmermann - One of the best experts on this subject based on the ideXlab platform.

  • Lipidomic data on lipid droplet Triglyceride remodelling associated with protection of breast cancer cells from lipotoxic stress
    Elsevier, 2018
    Co-Authors: Eva Jarc, Robert Zimmermann, Thomas O Eichmann, Toni Petan
    Abstract:

    The data presented here is related to the research article entitled “Lipid droplets induced by secreted phosphoLipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress” by E. Jarc et al., Biochim. Biophys. Acta 1863 (2018) 247–265. Elevated uptake of unsaturated fatty acids and lipid droplet accumulation are characteristic of aggressive cancer cells and have been associated with the cellular stress response. The present study provides lipidomic data on the triacylglycerol (TAG) and phosphatidylcholine (PC) composition of MDA-MB-231 breast cancer cells exposed to docosahexaenoic acid (DHA; 22:6, ω-3). Datasets provide information on the changes in lipid composition induced by depletion of Adipose Triglyceride Lipase (ATGL) and by exogenous addition of secreted phosphoLipase A2 (sPLA2) in DHA-treated cells. The presented alterations in lipid composition, mediated by targeting lipid droplet biogenesis and lipolysis, are associated with protection from lipotoxicity and allow further investigation into the role of lipid droplets in the resistance of cancer cells to lipotoxic stress. Keywords: Lipid droplets, Lipidomics, Adipose Triglyceride Lipase, Polyunsaturated fatty acid, Cancer, PhosphoLipase A

  • a peptide derived from g0 g1 switch gene 2 acts as noncompetitive inhibitor of Adipose Triglyceride Lipase
    Journal of Biological Chemistry, 2014
    Co-Authors: Ines K Cerk, Martina Schweiger, Achim Lass, Irina Cornaciu, Christoph Heier, Matthias Romauch, Barbara Salzburger, Andras Boeszoermenyi, Christoph Pillip, Robert Zimmermann
    Abstract:

    The protein G0/G1 switch gene 2 (G0S2) is a small basic protein that functions as an endogenous inhibitor of Adipose Triglyceride Lipase (ATGL), a key enzyme in intracellular lipolysis. In this study, we identified a short sequence covering residues Lys-20 to Ala-52 in G0S2 that is still fully capable of inhibiting mouse and human ATGL. We found that a synthetic peptide corresponding to this region inhibits ATGL in a noncompetitive manner in the nanomolar range. This peptide is highly selective for ATGL and does not inhibit other Lipases, including hormone-sensitive Lipase, monoacylglycerol Lipase, lipoprotein Lipase, and patatin domain-containing phosphoLipases 6 and 7. Because increased lipolysis is linked to the development of metabolic disorders, the inhibition of ATGL by G0S2-derived peptides may represent a novel therapeutic tool to modulate lipolysis.

  • Adipose Triglyceride Lipase activity is inhibited by long chain acyl coenzyme a
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Harald M Nagy, Achim Lass, Margret Paar, Guenter Haemmerle, Rudolf Zechner, Tarek Moustafa, Monika Oberer, Christoph Heier, Peter Hofer, Robert Zimmermann
    Abstract:

    Adipose Triglyceride Lipase (ATGL) is required for efficient mobilization of Triglyceride (TG) stores in Adipose tissue and non-Adipose tissues. Therefore, ATGL strongly determines the availability of fatty acids for metabolic reactions. ATGL activity is regulated by a complex network of lipolytic and anti-lipolytic hormones. These signals control enzyme expression and the interaction of ATGL with the regulatory proteins CGI-58 and G0S2. Up to date, it was unknown whether ATGL activity is also controlled by lipid intermediates generated during lipolysis. Here we show that ATGL activity is inhibited by long-chain acyl-CoAs in a non-competitive manner, similar as previously shown for hormone-sensitive Lipase (HSL), the rate-limiting enzyme for diglyceride breakdown in Adipose tissue. ATGL activity is only marginally inhibited by medium-chain acyl-CoAs, diglycerides, monoglycerides, and free fatty acids. Immunoprecipitation assays revealed that acyl-CoAs do not disrupt the protein–protein interaction of ATGL and its co-activator CGI-58. Furthermore, inhibition of ATGL is independent of the presence of CGI-58 and occurs directly at the N-terminal patatin-like phosphoLipase domain of the enzyme. In conclusion, our results suggest that inhibition of the major lipolytic enzymes ATGL and HSL by long-chain acyl-CoAs could represent an effective feedback mechanism controlling lipolysis and protecting cells from lipotoxic concentrations of fatty acids and fatty acid-derived lipid metabolites.

  • Role of Adipose Triglyceride Lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia.
    Hepatology (Baltimore Md.), 2014
    Co-Authors: Pooja Jha, Suman K. Das, Robert Zimmermann, Achim Lass, Rudolf Zechner, Thierry Claudel, Anna Baghdasaryan, Michaela Mueller, Emina Halilbasic, Gerald Hoefler
    Abstract:

    Hepatic inflammation is a key feature of progressive liver disease. Alterations of fatty acid (FA) metabolism and signaling may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Moreover, FAs activate peroxisome proliferator-activated receptor α (PPARα) as a key transcriptional regulator of hepatic FA metabolism and inflammation. Since Adipose Triglyceride Lipase (ATGL/PNPLA2) is the key enzyme for intracellular hydrolysis of stored Triglycerides and determines FA signaling through PPARα, we explored the role of ATGL in hepatic inflammation in mouse models of NASH and endotoxemia. Mice lacking ATGL or hormone-sensitive Lipase (HSL) were challenged with a methionine-choline-deficient (MCD) diet as a nutritional model of NASH or lipopolysaccharide (LPS) as a model of acute hepatic inflammation. We further tested whether a PPARα agonist (fenofibrate) treatment improves the hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice. MCD-fed ATGL-KO mice, although partially protected from peripheral lipolysis, showed exacerbated hepatic steatosis and inflammation. Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic inflammation, increased mortality, and torpor, findings which were attributed to impaired PPARα DNA binding activity due to reduced FABP1 protein levels, resulting in impaired nuclear FA import. Notably, liganding PPARα through fenofibrate attenuated hepatic inflammation in both MCD-fed and LPS-treated ATGL-KO mice. In contrast, mice lacking HSL had a phenotype similar to the WT mice on MCD and LPS challenge. Conclusion: These findings unravel a novel protective role of ATGL against hepatic inflammation which could have important implications for metabolic and inflammatory liver diseases. (Hepatology 2014;59:858–869)

  • studies on the substrate and stereo regioselectivity of Adipose Triglyceride Lipase hormone sensitive Lipase and diacylglycerol o acyltransferases
    Journal of Biological Chemistry, 2012
    Co-Authors: Thomas O Eichmann, Robert Zimmermann, Achim Lass, Manju Kumari, Joel T Haas, Robert V Farese, Rudolf Zechner
    Abstract:

    Adipose Triglyceride Lipase (ATGL) is rate-limiting for the initial step of triacylglycerol (TAG) hydrolysis, generating diacylglycerol (DAG) and fatty acids. DAG exists in three stereochemical isoforms. Here we show that ATGL exhibits a strong preference for the hydrolysis of long-chain fatty acid esters at the sn-2 position of the glycerol backbone. The selectivity of ATGL broadens to the sn-1 position upon stimulation of the enzyme by its co-activator CGI-58. sn-1,3 DAG is the preferred substrate for the consecutive hydrolysis by hormone-sensitive Lipase. Interestingly, diacylglycerol-O-acyltransferase 2, present at the endoplasmic reticulum and on lipid droplets, preferentially esterifies sn-1,3 DAG. This suggests that ATGL and diacylglycerol-O-acyltransferase 2 act coordinately in the hydrolysis/re-esterification cycle of TAGs on lipid droplets. Because ATGL preferentially generates sn-1,3 and sn-2,3, it suggests that TAG-derived DAG cannot directly enter phospholipid synthesis or activate protein kinase C without prior isomerization.

Guenter Haemmerle - One of the best experts on this subject based on the ideXlab platform.

  • endothelial dysfunction in Adipose Triglyceride Lipase deficiency
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Astrid Schrammel, Martina Schweiger, Guenter Haemmerle, Marion Mussbacher, Gerald Wolkart, Heike Stessel, Karoline Pail, Sarah Winkler, Wael Al Zoughbi, Gerald Hofler
    Abstract:

    Systemic knockout of Adipose Triglyceride Lipase (ATGL), the pivotal enzyme of Triglyceride lipolysis, results in a murine phenotype that is characterized by progredient cardiac steatosis and severe heart failure. Since cardiac and vascular dysfunction have been closely related in numerous studies we investigated endothelium-dependent and -independent vessel function of ATGL knockout mice. Aortic relaxation studies and Langendorff perfusion experiments of isolated hearts showed that ATGL knockout mice suffer from pronounced micro- and macrovascular endothelial dysfunction. Experiments with agonists directly targeting vascular smooth muscle cells revealed the functional integrity of the smooth muscle cell layer. Loss of vascular reactivity was restored ~50% upon treatment of ATGL knockout mice with the PPARα agonist Wy14,643, indicating that this phenomenon is partly a consequence of impaired cardiac contractility. Biochemical analysis revealed that aortic endothelial NO synthase expression and activity were significantly reduced in ATGL deficiency. Enzyme activity was fully restored in ATGL mice treated with the PPARα agonist. Biochemical analysis of perivascular Adipose tissue demonstrated that ATGL knockout mice suffer from perivascular inflammatory oxidative stress which occurs independent of cardiac dysfunction and might contribute to vascular defects. Our results reveal a hitherto unrecognized link between disturbed lipid metabolism, obesity and cardiovascular disease.

  • Adipose Triglyceride Lipase activity is inhibited by long chain acyl coenzyme a
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Harald M Nagy, Achim Lass, Margret Paar, Guenter Haemmerle, Rudolf Zechner, Tarek Moustafa, Monika Oberer, Christoph Heier, Peter Hofer, Robert Zimmermann
    Abstract:

    Adipose Triglyceride Lipase (ATGL) is required for efficient mobilization of Triglyceride (TG) stores in Adipose tissue and non-Adipose tissues. Therefore, ATGL strongly determines the availability of fatty acids for metabolic reactions. ATGL activity is regulated by a complex network of lipolytic and anti-lipolytic hormones. These signals control enzyme expression and the interaction of ATGL with the regulatory proteins CGI-58 and G0S2. Up to date, it was unknown whether ATGL activity is also controlled by lipid intermediates generated during lipolysis. Here we show that ATGL activity is inhibited by long-chain acyl-CoAs in a non-competitive manner, similar as previously shown for hormone-sensitive Lipase (HSL), the rate-limiting enzyme for diglyceride breakdown in Adipose tissue. ATGL activity is only marginally inhibited by medium-chain acyl-CoAs, diglycerides, monoglycerides, and free fatty acids. Immunoprecipitation assays revealed that acyl-CoAs do not disrupt the protein–protein interaction of ATGL and its co-activator CGI-58. Furthermore, inhibition of ATGL is independent of the presence of CGI-58 and occurs directly at the N-terminal patatin-like phosphoLipase domain of the enzyme. In conclusion, our results suggest that inhibition of the major lipolytic enzymes ATGL and HSL by long-chain acyl-CoAs could represent an effective feedback mechanism controlling lipolysis and protecting cells from lipotoxic concentrations of fatty acids and fatty acid-derived lipid metabolites.

  • early structural and metabolic cardiac remodelling in response to inducible Adipose Triglyceride Lipase ablation
    Cardiovascular Research, 2013
    Co-Authors: Petra C. Kienesberger, Juliane G Bognerstrauss, Thomas Pulinilkunnil, Martin E Young, Guenter Haemmerle, J Nagendran, Hubert Hackl, Rammy Khadour, Emma Heydari, Rudolf Zechner
    Abstract:

    Aims While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as Adipose Triglyceride Lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor α (PPARα) activity and subsequent fatty acid oxidation (FAO). However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARα activity, cardiac function, and metabolism is not known. Methods and results To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (ic Atgl KO). Within 4–6 weeks following ATGL ablation, ic Atgl KO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in ic Atgl KO mice. Analysis of energy metabolism in e x vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression. Conclusions This study shows that acquired cardiomyocyte-specific ATGL deficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARα signalling.

  • myocardial Adipose Triglyceride Lipase overexpression protects diabetic mice from the development of lipotoxic cardiomyopathy
    Diabetes, 2013
    Co-Authors: Thomas Pulinilkunnil, Petra C. Kienesberger, Martin E Young, Guenter Haemmerle, Rudolf Zechner, Erin E. Kershaw, Jayan Nagendran, Terri J Waller, Gregory S Korbutt, Jason R B Dyck
    Abstract:

    Although diabetic cardiomyopathy is associated with enhanced intramyocardial triacylglycerol (TAG) levels, the role of TAG catabolizing enzymes in this process is unclear. Because the TAG hydrolase, Adipose Triglyceride Lipase (ATGL), regulates baseline cardiac metabolism and function, we examined whether alterations in cardiomyocyte ATGL impact cardiac function during uncontrolled type 1 diabetes. In genetic (Akita) and pharmacological (streptozotocin) murine models of type 1 diabetes, cardiac ATGL protein expression and TAG content were significantly increased. To determine whether increased ATGL expression during diabetes is detrimental or beneficial to cardiac function, we studied streptozotocin-diabetic mice with heterozygous ATGL deficiency and cardiomyocyte-specific ATGL overexpression. After diabetes, streptozotocin-diabetic mice with heterozygous ATGL deficiency displayed increased TAG accumulation, lipotoxicity, and diastolic dysfunction comparable to wild-type mice. In contrast, myosin heavy chain promoter (MHC)-ATGL mice were resistant to diabetes-induced increases in intramyocardial TAG levels, lipotoxicity, and cardiac dysfunction. Moreover, hearts from diabetic MHC-ATGL mice exhibited decreased reliance on palmitate oxidation and blunted peroxisome proliferator--activated receptor-α activation. Collectively, this study shows that after diabetes, increased cardiac ATGL expression is an adaptive, albeit insufficient, response to compensate for the accumulation of myocardial TAG, and that overexpression of ATGL is sufficient to ameliorate diabetes-induced cardiomyopathy.

  • Adipose Triglyceride Lipase (ATGL) and Hormone-Sensitive Lipase (HSL) Deficiencies Affect Expression of Lipolytic Activities in Mouse Adipose Tissues
    Molecular & cellular proteomics : MCP, 2012
    Co-Authors: Maria Morak, Guenter Haemmerle, Rudolf Zechner, Hannes Schmidinger, Gernot Riesenhuber, Gerald N. Rechberger, Manfred Kollroser, Florian Kronenberg, Albin Hermetter
    Abstract:

    Adipose Triglyceride Lipase (ATGL) and hormone-sensitive Lipase (HSL) are key enzymes involved in intracellular degradation of triacylglycerols. It was the aim of this study to elucidate how the deficiency in one of these proteins affects the residual lipolytic proteome in Adipose tissue. For this purpose, we compared the Lipase patters of brown and white Adipose tissue from ATGL (−/−) and HSL (−/−) mice using differential activity-based gel electrophoresis. This method is based on activity-recognition probes possessing the same substrate analogous structure but carrying different fluorophores for specific detection of the enzyme patterns of two different tissues in one electrophoresis gel. We found that ATGL-deficiency in brown Adipose tissue had a profound effect on the expression levels of other lipolytic and esterolytic enzymes in this tissue, whereas HSL-deficiency hardly showed any effect in brown Adipose tissue. Neither ATGL- nor HSL-deficiency greatly influenced the Lipase patterns in white Adipose tissue. Enzyme activities of mouse tissues on acylglycerol substrates were analyzed as well, showing that ATGL-and HSL-deficiencies can be compensated for at least in part by other enzymes. The proteins that responded to ATGL-deficiency in brown Adipose tissue were overexpressed and their activities on acylglycerols were analyzed. Among these enzymes, Es1, Es10, and Es31-like represent Lipase candidates as they catalyze the hydrolysis of long-chain acylglycerols.