Heier C

References (16)

Title : The Patatin-Like Phospholipase Domain Containing Protein 7 Regulates Macrophage Classical Activation through SIRT1\/NF-B and p38 MAPK Pathways - Zhao_2022_Int.J.Mol.Sci_23_
Author(s) : Zhao Z , Heier C , Pang H , Wang Y , Huang F , Chang P
Ref : Int J Mol Sci , 23 : , 2022
Abstract : Lysophosphatidylcholine (LPC) is a bioactive lipid that modulates macrophage polarization during immune responses, inflammation, and tissue remodeling. Patatin-like phospholipase domain containing protein 7 (PNPLA7) is a lysophospholipase with a preference for LPC. However, the role of PNPLA7 in macrophage polarization as an LPC hydrolase has not been explored. In the current study, we found that PNPLA7 is highly expressed in naive macrophages and downregulated upon lipopolysaccharide (LPS)-induced polarization towards the classically activated (M1) phenotype. Consistently, overexpression of PNPLA7 suppressed the expression of proinflammatory M1 marker genes, including interleukin 1beta (IL-1beta), IL-6, inducible nitric oxide synthase (iNOS), and tumor necrosis factor alpha (TNF-alpha), whereas knockdown of PNPLA7 augmented the inflammatory gene expression in LPS-challenged macrophages. PNPLA7 overexpression and knockdown increased and decreased Sirtuin1 (SIRT1) mRNA and protein levels, respectively, and affected the acetylation of the nuclear factor-kappa B (NF-kappaB) p65 subunit, a key transcription factor in M1 polarization. In addition, the levels of phosphorylated p38 mitogen-activated protein kinase (MAPK) were suppressed and enhanced by PNPLA7 overexpression and knockdown, respectively. Taken together, these findings suggest that PNPLA7 suppresses M1 polarization of LPS-challenged macrophages by modulating SIRT1/NF-kappaB- and p38 MAPK-dependent pathways.
ESTHER : Zhao_2022_Int.J.Mol.Sci_23_
PubMedSearch : Zhao_2022_Int.J.Mol.Sci_23_
PubMedID: 36499308

Title : Drosophila Lipase 3 Mediates the Metabolic Response to Starvation and Aging - Hanschke_2022_Front.Aging_3_800153
Author(s) : Hanschke L , Heier C , Maya Palacios SJ , Ozek HE , Thiele C , Bauer R , Kuhnlein RP , Bulow MH
Ref : Front Aging , 3 :800153 , 2022
Abstract : The human LIPA gene encodes for the enzyme lysosomal acid lipase, which hydrolyzes cholesteryl ester and triacylglycerol. Lysosomal acid lipase deficiency results in Wolman disease and cholesteryl ester storage disease. The Drosophila genome encodes for two LIPA orthologs, Magro and Lipase 3. Magro is a gut lipase that hydrolyzes triacylglycerides, while Lipase 3 lacks characterization based on mutant phenotypes. We found previously that Lipase 3 transcription is highly induced in mutants with defects in peroxisome biogenesis, but the conditions that allow a similar induction in wildtypic flies are not known. Here we show that Lipase 3 is drastically upregulated in starved larvae and starved female flies, as well as in aged male flies. We generated a lipase 3 mutant that shows sex-specific starvation resistance and a trend to lifespan extension. Using lipidomics, we demonstrate that Lipase 3 mutants accumulate phosphatidylinositol, but neither triacylglycerol nor diacylglycerol. Our study suggests that, in contrast to its mammalian homolog LIPA, Lipase 3 is a putative phospholipase that is upregulated under extreme conditions like prolonged nutrient deprivation and aging.
ESTHER : Hanschke_2022_Front.Aging_3_800153
PubMedSearch : Hanschke_2022_Front.Aging_3_800153
PubMedID: 35821816
Gene_locus related to this paper: drome-lip3

Title : Hormone-sensitive lipase couples intergenerational sterol metabolism to reproductive success - Heier_2021_Elife_10_
Author(s) : Heier C , Knittelfelder O , Hofbauer HF , Mende W , Pornbacher I , Schiller L , Schoiswohl G , Xie H , Gronke S , Shevchenko A , Kuhnlein RP
Ref : Elife , 10 : , 2021
Abstract : Triacylglycerol (TG) and steryl ester (SE) lipid storage is a universal strategy to maintain organismal energy and membrane homeostasis. Cycles of building and mobilizing storage fat are fundamental in (re)distributing lipid substrates between tissues or to progress ontogenetic transitions. In this study we show that Hormone-sensitive lipase (Hsl) specifically controls SE mobilization to initiate intergenerational sterol transfer in Drosophila melanogaster. Tissue-autonomous Hsl functions in the maternal fat body and germline coordinately prevent adult SE overstorage and maximize sterol allocation to embryos. While Hsl-deficiency is largely dispensable for normal development on sterol-rich diets, animals depend on adipocyte Hsl for optimal fecundity when dietary sterol becomes limiting. Notably, accumulation of SE but not of TG is a characteristic of Hsl-deficient cells across phyla including murine white adipocytes. In summary, we identified Hsl as an ancestral regulator of SE degradation, which improves intergenerational sterol transfer and reproductive success in flies.
ESTHER : Heier_2021_Elife_10_
PubMedSearch : Heier_2021_Elife_10_
PubMedID: 33538247

Title : Optimized expression and purification of adipose triglyceride lipase improved hydrolysis and transacylation catalytic activities in vitro - Kulminskaya_2021_J.Biol.Chem__101206
Author(s) : Kulminskaya N , Radler C , Viertlmayr R , Heier C , Hofer P , Colaco-Gaspar M , Owens RJ , Zimmermann R , Schreiber R , Zechner R , Oberer M
Ref : Journal of Biological Chemistry , :101206 , 2021
Abstract : Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis, the mobilization of stored triacylglycerol. This work provides an important basis for generating reproducible and detailed data on the hydrolytic and transacylation activities of ATGL. We generated full-length and C-terminally truncated ATGL variants fused with various affinity tags and analyzed their expression in different hosts, namely E. coli, the insect cell line Sf9, and the mammalian cell line HEK 293T. Based on this screen, we expressed a fusion protein of ATGL covering residues M1 to D288 flanked with N- and C-terminal purification tags. Using these fusions, we identified key steps in expression and purification protocols, including production in the E. coli strain ArcticExpress (DE3) and removal of co-purified chaperones. The resulting purified ATGL variant demonstrated improved lipolytic activity compared to previously published data, and it could be stimulated by the co-activator protein comparative gene identification 58 (CGI-58) and inhibited by the protein G0/G1 switch protein 2 (G0S2). Shock-freezing and storage did not affect the basal activity, but reduced co-activation of ATGL by CGI-58. In vitro, the truncated ATGL variant demonstrated acyl-CoA-independent transacylation activity when diacylglycerol was offered as substrate, resulting in the formation of fatty acid as well as tri- and monoacylglycerol. However, the ATGL variant neither showed hydrolytic nor transacylation activity upon offering of monoacylglycerol as substrate. To understand the role of ATGL in different physiological contexts, it is critical for future studies to identify all its different functions and to determine under what conditions these activities occur.
ESTHER : Kulminskaya_2021_J.Biol.Chem__101206
PubMedSearch : Kulminskaya_2021_J.Biol.Chem__101206
PubMedID: 34543623

Title : Enhanced monoacylglycerol lipolysis by ABHD6 promotes NSCLC pathogenesis - Tang_2020_EBioMedicine_53_102696
Author(s) : Tang Z , Xie H , Heier C , Huang J , Zheng Q , Eichmann TO , Schoiswohl G , Ni J , Zechner R , Ni S , Hao H
Ref : EBioMedicine , 53 :102696 , 2020
Abstract : BACKGROUND: Tumor cells display metabolic changes that correlate with malignancy, including an elevated hydrolysis of monoacylglycerol (MAG) in various cancer types. However, evidence is absent for the relationship between MAG lipolysis and NSCLC. METHODS: MAG hydrolase activity assay, migration, invasion, proliferation, lipids quantification, and transactivation assays were performed in vitro. Tumor xenograft studies and lung metastasis assays were examined in vivo. The correlations of MAGL/ABHD6 expression in cancerous tissues with the clinicopathological characteristics and survival of NSCLC patients were validated. FINDINGS: ABHD6 functions as the primary MAG lipase and an oncogene in NSCLC. MAG hydrolase activities were more than 11-fold higher in cancerous lung tissues than in paired non-cancerous tissues derived from NSCLC patients. ABHD6, instead of MAGL, was significantly associated with advanced tumor node metastasis (TNM) stage (HR, 1.382; P = 0.004) and had a negative impact on the overall survival of NSCLC patients (P = 0.001). ABHD6 silencing reduced migration and invasion of NSCLC cells in vitro as well as metastatic seeding and tumor growth in vivo. Conversely, ectopic overexpression of ABHD6 provoked the pathogenic potential. ABHD6 blockade significantly induced intracellular MAG accumulation which activated PPARalpha/gamma signaling and inhibited cancer pathophysiology. INTERPRETATION: The present study provide evidence for a previously uncovered pro-oncogenic function of ABHD6 in NSCLC, with the outlined metabolic mechanisms shedding light on new potential strategies for anticancer therapy. FUND: This work was supported by the Project for Major New Drug Innovation and Development (2015ZX09501010 and 2018ZX09711001-002-003).
ESTHER : Tang_2020_EBioMedicine_53_102696
PubMedSearch : Tang_2020_EBioMedicine_53_102696
PubMedID: 32143183

Title : The alpha\/beta-hydrolase domain-containing 4- and 5-related phospholipase Pummelig controls energy storage in Drosophila - Hehlert_2019_J.Lipid.Res_60_1365
Author(s) : Hehlert P , Hofferek V , Heier C , Eichmann TO , Riedel D , Rosenberg J , Takacs A , Nagy HM , Oberer M , Zimmermann R , Kuhnlein RP
Ref : J Lipid Res , 60 :1365 , 2019
Abstract : Triglycerides (TGs) are the main energy storage form that accommodates changing organismal energy demands. In Drosophila melanogaster, the TG lipase Brummer is centrally important for body fat mobilization. Its gene brummer (bmm) encodes the ortholog of mammalian adipose TG lipase, which becomes activated by alpha/beta-hydrolase domain-containing 5 (ABHD5/CGI-58), one member of the paralogous gene pair, alpha/beta-hydrolase domain-containing 4 (ABHD4) and ABHD5 In Drosophila, the pummelig (puml) gene encodes the single sequence-related protein to mammalian ABHD4/ABHD5 with unknown function. We generated puml deletion mutant flies, that were short-lived as a result of lipid metabolism changes, stored excess body fat at the expense of glycogen, and exhibited ectopic fat storage with altered TG FA profile in the fly kidneys, called Malpighian tubules. TG accumulation in puml mutants was not associated with increased food intake but with elevated lipogenesis; starvation-induced lipid mobilization remained functional. Despite its structural similarity to mammalian ABHD5, Puml did not stimulate TG lipase activity of Bmm in vitro. Rather, Puml acted as a phospholipase that localized on lipid droplets, mitochondria, and peroxisomes. Together, these results show that the ABHD4/5 family member Puml is a versatile phospholipase that regulates Drosophila body fat storage and energy metabolism.
ESTHER : Hehlert_2019_J.Lipid.Res_60_1365
PubMedSearch : Hehlert_2019_J.Lipid.Res_60_1365
PubMedID: 31164391
Gene_locus related to this paper: drome-CG1882

Title : Hypoxia-inducible lipid droplet-associated protein inhibits adipose triglyceride lipase - Padmanabha_2018_J.Lipid.Res_59_531
Author(s) : Padmanabha Das KM , Wechselberger L , Liziczai M , De la Rosa Rodriguez M , Grabner GF , Heier C , Viertlmayr R , Radler C , Lichtenegger J , Zimmermann R , Borst JW , Zechner R , Kersten S , Oberer M
Ref : J Lipid Res , 59 :531 , 2018
Abstract : Elaborate control mechanisms of intracellular triacylglycerol (TAG) breakdown are critically involved in the maintenance of energy homeostasis. Hypoxia-inducible lipid droplet-associated protein (HILPDA)/hypoxia-inducible gene-2 (Hig-2) has been shown to affect intracellular TAG levels, yet, the underlying molecular mechanisms are unclear. Here, we show that HILPDA inhibits adipose triglyceride lipase (ATGL), the enzyme catalyzing the first step of intracellular TAG hydrolysis. HILPDA shares structural similarity with G0/G1 switch gene 2 (G0S2), an established inhibitor of ATGL. HILPDA inhibits ATGL activity in a dose-dependent manner with an IC50 value of approximately 2 muM. ATGL inhibition depends on the direct physical interaction of both proteins and involves the N-terminal hydrophobic region of HILPDA and the N-terminal patatin domain-containing segment of ATGL. Finally, confocal microscopy combined with Forster resonance energy transfer-fluorescence lifetime imaging microscopy analysis indicated that HILPDA and ATGL colocalize and physically interact intracellularly. These findings provide a rational biochemical explanation for the tissue-specific increased TAG accumulation in HILPDA-overexpressing transgenic mouse models.
ESTHER : Padmanabha_2018_J.Lipid.Res_59_531
PubMedSearch : Padmanabha_2018_J.Lipid.Res_59_531
PubMedID: 29326160

Title : Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation - Grond_2017_J.Invest.Dermatol_137_403
Author(s) : Grond S , Radner FP , Eichmann TO , Kolb D , Grabner GF , Wolinski H , Gruber R , Hofer P , Heier C , Schauer S , Rulicke T , Hoefler G , Schmuth M , Elias PM , Lass A , Zechner R , Haemmerle G
Ref : Journal of Investigative Dermatology , 137 :403 , 2017
Abstract : Adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) are limiting in cellular triglyceride catabolism. Although ATGL deficiency is compatible with normal skin development, mice globally lacking CGI-58 die postnatally and exhibit a severe epidermal permeability barrier defect, which may originate from epidermal and/or peripheral changes in lipid and energy metabolism. Here, we show that epidermis-specific disruption of CGI-58 is sufficient to provoke a defect in the formation of a functional corneocyte lipid envelope linked to impaired omega-O-acylceramide synthesis. As a result, epidermis-specific CGI-58-deficient mice show severe skin dysfunction, arguing for a tissue autonomous cause of disease development. Defective skin permeability barrier formation in global CGI-58-deficient mice could be reversed via transgenic restoration of CGI-58 expression in differentiated but not basal keratinocytes suggesting that CGI-58 is essential for lipid metabolism in suprabasal epidermal layers. The compatibility of ATGL deficiency with normal epidermal function indicated that CGI-58 may stimulate an epidermal triglyceride lipase beyond ATGL required for the adequate provision of fatty acids as a substrate for omega-O-acylceramide synthesis. Pharmacological inhibition of ATGL enzyme activity similarly reduced triglyceride-hydrolytic activities in wild-type and CGI-58 overexpressing epidermis implicating that CGI-58 participates in omega-O-acylceramide biogenesis independent of its role as a coactivator of epidermal triglyceride catabolism.
ESTHER : Grond_2017_J.Invest.Dermatol_137_403
PubMedSearch : Grond_2017_J.Invest.Dermatol_137_403
PubMedID: 27725204
Gene_locus related to this paper: human-ABHD5

Title : Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism - Heier_2016_J.Biol.Chem_291_11865
Author(s) : Heier C , Taschler U , Radulovic M , Aschauer P , Eichmann TO , Grond S , Wolinski H , Oberer M , Zechner R , Kohlwein SD , Zimmermann R
Ref : Journal of Biological Chemistry , 291 :11865 , 2016
Abstract : Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study, we used a biochemical screen in Saccharomyces cerevisiae to identify and characterize putative hydrolases involved in FAEE catabolism. We found that Yju3p, the functional orthologue of mammalian monoacylglycerol lipase (MGL), contributes >90% of cellular FAEE hydrolase activity, and its loss leads to the accumulation of FAEE. Heterologous expression of mammalian MGL in yju3Delta mutants restored cellular FAEE hydrolase activity and FAEE catabolism. Moreover, overexpression or pharmacological inhibition of MGL in mouse AML-12 hepatocytes decreased or increased FAEE levels, respectively. FAEEs were transiently incorporated into lipid droplets (LDs) and both Yju3p and MGL co-localized with these organelles. We conclude that the storage of FAEE in inert LDs and their mobilization by LD-resident FAEE hydrolases facilitate a controlled metabolism of these potentially toxic lipid metabolites.
ESTHER : Heier_2016_J.Biol.Chem_291_11865
PubMedSearch : Heier_2016_J.Biol.Chem_291_11865
PubMedID: 27036938

Title : ATGL and CGI-58 are lipid droplet proteins of the hepatic stellate cell line HSC-T6 - Eichmann_2015_J.Lipid.Res_56_1972
Author(s) : Eichmann TO , Grumet L , Taschler U , Hartler J , Heier C , Woblistin A , Pajed L , Kollroser M , Rechberger G , Thallinger GG , Zechner R , Haemmerle G , Zimmermann R , Lass A
Ref : J Lipid Res , 56 :1972 , 2015
Abstract : Lipid droplets (LDs) of hepatic stellate cells (HSCs) contain large amounts of vitamin A [in the form of retinyl esters (REs)] as well as other neutral lipids such as TGs. During times of insufficient vitamin A availability, RE stores are mobilized to ensure a constant supply to the body. To date, little is known about the enzymes responsible for the hydrolysis of neutral lipid esters, in particular of REs, in HSCs. In this study, we aimed to identify LD-associated neutral lipid hydrolases by a proteomic approach using the rat stellate cell line HSC-T6. First, we loaded cells with retinol and FAs to promote lipid synthesis and deposition within LDs. Then, LDs were isolated and lipid composition and the LD proteome were analyzed. Among other proteins, we found perilipin 2, adipose TG lipase (ATGL), and comparative gene identification-58 (CGI-58), known and established LD proteins. Bioinformatic search of the LD proteome for alpha/beta-hydrolase fold-containing proteins revealed no yet uncharacterized neutral lipid hydrolases. In in vitro activity assays, we show that rat (r)ATGL, coactivated by rat (r)CGI-58, efficiently hydrolyzes TGs and REs. These findings suggest that rATGL and rCGI-58 are LD-resident proteins in HSCs and participate in the mobilization of both REs and TGs.
ESTHER : Eichmann_2015_J.Lipid.Res_56_1972
PubMedSearch : Eichmann_2015_J.Lipid.Res_56_1972
PubMedID: 26330055
Gene_locus related to this paper: human-ABHD5

Title : alpha\/beta Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal\/Lysosomal Lipid Bis(monoacylglycero)phosphate - Pribasnig_2015_J.Biol.Chem_290_29869
Author(s) : Pribasnig MA , Mrak I , Grabner GF , Taschler U , Knittelfelder O , Scherz B , Eichmann TO , Heier C , Grumet L , Kowaliuk J , Romauch M , Holler S , Anderl F , Wolinski H , Lass A , Breinbauer R , Marsche G , Brown JM , Zimmermann R
Ref : Journal of Biological Chemistry , 290 :29869 , 2015
Abstract : alpha/beta Hydrolase domain-containing 6 (ABHD6) can act as monoacylglycerol hydrolase and is believed to play a role in endocannabinoid signaling as well as in the pathogenesis of obesity and liver steatosis. However, the mechanistic link between gene function and disease is incompletely understood. Here we aimed to further characterize the role of ABHD6 in lipid metabolism. We show that mouse and human ABHD6 degrade bis(monoacylglycero)phosphate (BMP) with high specific activity. BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes/lysosomes, where it plays a key role in the formation of intraluminal vesicles and in lipid sorting. Up to now, little has been known about the catabolism of this lipid. Our data demonstrate that ABHD6 is responsible for approximately 90% of the BMP hydrolase activity detected in the liver and that knockdown of ABHD6 increases hepatic BMP levels. Tissue fractionation and live-cell imaging experiments revealed that ABHD6 co-localizes with late endosomes/lysosomes. The enzyme is active at cytosolic pH and lacks acid hydrolase activity, implying that it degrades BMP exported from acidic organelles or de novo-formed BMP. In conclusion, our data suggest that ABHD6 controls BMP catabolism and is therefore part of the late endosomal/lysosomal lipid-sorting machinery.
ESTHER : Pribasnig_2015_J.Biol.Chem_290_29869
PubMedSearch : Pribasnig_2015_J.Biol.Chem_290_29869
PubMedID: 26491015
Gene_locus related to this paper: human-ABHD6

Title : Adipose triglyceride lipase activity is inhibited by long-chain acyl-coenzyme A - Nagy_2014_Biochim.Biophys.Acta_1841_588
Author(s) : Nagy HM , Paar M , Heier C , Moustafa T , Hofer P , Haemmerle G , Lass A , Zechner R , Oberer M , Zimmermann R
Ref : Biochimica & Biophysica Acta , 1841 :588 , 2014
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.
ESTHER : Nagy_2014_Biochim.Biophys.Acta_1841_588
PubMedSearch : Nagy_2014_Biochim.Biophys.Acta_1841_588
PubMedID: 24440819

Title : The evolutionarily conserved protein CG9186 is associated with lipid droplets, required for their positioning and for fat storage - Thiel_2013_J.Cell.Sci_126_2198
Author(s) : Thiel K , Heier C , Haberl V , Thul PJ , Oberer M , Lass A , Jackle H , Beller M
Ref : Journal of Cell Science , 126 :2198 , 2013
Abstract : Lipid droplets (LDs) are specialized cell organelles for the storage of energy-rich lipids. Although lipid storage is a conserved feature of all cells and organisms, 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 evolutionarily conserved targeting mechanism that acts through a 60-amino-acid 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 RNAi knockdown of CG9186 results in a reduction of LDs. Organismal RNAi knockdown of CG9186 results in a reduction in lipid storage levels of the fly. The results indicate that we identified the first members of a novel and evolutionarily conserved family of lipid storage regulators, which are also required to properly position LDs within cells.
ESTHER : Thiel_2013_J.Cell.Sci_126_2198
PubMedSearch : Thiel_2013_J.Cell.Sci_126_2198
PubMedID: 23525007
Gene_locus related to this paper: drome-CG9186

Title : The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome - Thomas_2013_Cell.Rep_5_508
Author(s) : Thomas G , Betters JL , Lord CC , Brown AL , Marshall S , Ferguson D , Sawyer J , Davis MA , Melchior JT , Blume LC , Howlett AC , Ivanova PT , Milne SB , Myers DS , Mrak I , Leber V , Heier C , Taschler U , Blankman JL , Cravatt BF , Lee RG , Crooke RM , Graham MJ , Zimmermann R , Brown HA , Brown JM
Ref : Cell Rep , 5 :508 , 2013
Abstract : The serine hydrolase alpha/beta hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6's role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
ESTHER : Thomas_2013_Cell.Rep_5_508
PubMedSearch : Thomas_2013_Cell.Rep_5_508
PubMedID: 24095738
Gene_locus related to this paper: human-ABHD6

Title : Development of small-molecule inhibitors targeting adipose triglyceride lipase - Mayer_2013_Nat.Chem.Biol_9_785
Author(s) : Mayer N , Schweiger M , Romauch M , Grabner GF , Eichmann TO , Fuchs E , Ivkovic J , Heier C , Mrak I , Lass A , Hofler G , Fledelius C , Zechner R , Zimmermann R , Breinbauer R
Ref : Nat Chemical Biology , 9 :785 , 2013
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.
ESTHER : Mayer_2013_Nat.Chem.Biol_9_785
PubMedSearch : Mayer_2013_Nat.Chem.Biol_9_785
PubMedID: 24096302

Title : Identification of Yju3p as functional orthologue of mammalian monoglyceride lipase in the yeast Saccharomycescerevisiae - Heier_2010_Biochim.Biophys.Acta_1801_1063
Author(s) : Heier C , Taschler U , Rengachari S , Oberer M , Wolinski H , Natter K , Kohlwein SD , Leber R , Zimmermann R
Ref : Biochimica & Biophysica Acta , 1801 :1063 , 2010
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.
ESTHER : Heier_2010_Biochim.Biophys.Acta_1801_1063
PubMedSearch : Heier_2010_Biochim.Biophys.Acta_1801_1063
PubMedID: 20554061
Gene_locus related to this paper: human-MGLL , mouse-MGLL , yeast-mgll