Schoiswohl G

References (17)

Title : Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting - Steinhoff_2024_EMBO.Rep__
Author(s) : Steinhoff JS , Wagner C , Dahnhardt HE , Kosic K , Meng Y , Taschler U , Pajed L , Yang N , Wulff S , Kiefer MF , Petricek KM , Flores RE , Li C , Dittrich S , Sommerfeld M , Guillou H , Henze A , Raila J , Wowro SJ , Schoiswohl G , Lass A , Schupp M
Ref : EMBO Rep , : , 2024
Abstract : Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.
ESTHER : Steinhoff_2024_EMBO.Rep__
PubMedSearch : Steinhoff_2024_EMBO.Rep__
PubMedID: 38769419
Gene_locus related to this paper: human-LIPE

Title : Carboxylesterase 2a deletion provokes hepatic steatosis and insulin resistance in mice involving impaired diacylglycerol and lysophosphatidylcholine catabolism - Chalhoub_2023_Mol.Metab__101725
Author(s) : Chalhoub G , Jamnik A , Pajed L , Kolleritsch S , Hois V , Bagaric A , Prem D , Tilp A , Kolb D , Wolinski H , Taschler U , Zullig T , Rechberger GN , Fuchs C , Trauner M , Schoiswohl G , Haemmerle G
Ref : Mol Metab , :101725 , 2023
Abstract : OBJECTIVE: Hepatic triacylglycerol accumulation and insulin resistance are key features of NAFLD. However, NAFLD development and progression are rather triggered by the aberrant generation of lipid metabolites and signaling molecules including diacylglycerol (DAG) and lysophosphatidylcholine (lysoPC). Recent studies showed decreased expression of carboxylesterase 2 (CES2) in the liver of NASH patients and hepatic DAG accumulation was linked to low CES2 activity in obese individuals. The mouse genome encodes several Ces2 genes with Ces2a showing highest expression in the liver. Herein we investigated the role of mouse Ces2a and human CES2 in lipid metabolism in vivo and in vitro. METHODS: Lipid metabolism and insulin signaling were investigated in mice lacking Ces2a and in a human liver cell line upon pharmacological CES2 inhibition. Lipid hydrolytic activities were determined in vivo and from recombinant proteins. RESULTS: Ces2a deficient mice (Ces2a-ko) are obese and feeding a high-fat diet (HFD) provokes severe hepatic steatosis and insulin resistance together with elevated inflammatory and fibrotic gene expression. Lipidomic analysis revealed a marked rise in DAG and lysoPC levels in the liver of Ces2a-ko mice fed HFD. Hepatic lipid accumulation in Ces2a deficiency is linked to lower DAG and lysoPC hydrolytic activities in liver microsomal preparations. Moreover, Ces2a deficiency significantly increases hepatic expression and activity of MGAT1, a PPAR gamma target gene, suggesting aberrant lipid signaling upon Ces2a deficiency. Mechanistically, we found that recombinant Ces2a and CES2 show significant hydrolytic activity towards lysoPC (and DAG) and pharmacological inhibition of CES2 in human HepG2 cells largely phenocopies the lipid metabolic changes present in Ces2a-ko mice including reduced lysoPC and DAG hydrolysis, DAG accumulation and impaired insulin signaling. CONCLUSIONS: Ces2a and CES2 are critical players in hepatic lipid signaling likely via the hydrolysis of DAG and lysoPC at the ER.
ESTHER : Chalhoub_2023_Mol.Metab__101725
PubMedSearch : Chalhoub_2023_Mol.Metab__101725
PubMedID: 37059417
Gene_locus related to this paper: mouse-Ces2a

Title : The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1 - Eisner_2022_Int.J.Mol.Sci_23_13101
Author(s) : Eisner H , Riegler-Berket L , Gamez CFR , Sagmeister T , Chalhoub G , Darnhofer B , Jazleena PJ , Birner-Gruenberger R , Pavkov-Keller T , Haemmerle G , Schoiswohl G , Oberer M
Ref : Int J Mol Sci , 23 : , 2022
Abstract : Members of the carboxylesterase 2 (Ces2/CES2) family have been studied intensively with respect to their hydrolytic function on (pro)drugs, whereas their physiological role in lipid and energy metabolism has been realized only within the last few years. Humans have one CES2 gene which is highly expressed in liver, intestine, and kidney. Interestingly, eight homologous Ces2 (Ces2a to Ces2h) genes exist in mice and the individual roles of the corresponding proteins are incompletely understood. Mouse Ces2c (mCes2c) is suggested as potential ortholog of human CES2. Therefore, we aimed at its structural and biophysical characterization. Here, we present the first crystal structure of mCes2c to 2.12 resolution. The overall structure of mCes2c resembles that of the human CES1 (hCES1). The core domain adopts an alpha/beta hydrolase-fold with S230, E347, and H459 forming a catalytic triad. Access to the active site is restricted by the cap, the flexible lid, and the regulatory domain. The conserved gate (M417) and switch (F418) residues might have a function in product release similar as suggested for hCES1. Biophysical characterization confirms that mCes2c is a monomer in solution. Thus, this study broadens our understanding of the mammalian carboxylesterase family and assists in delineating the similarities and differences of the different family members.
ESTHER : Eisner_2022_Int.J.Mol.Sci_23_13101
PubMedSearch : Eisner_2022_Int.J.Mol.Sci_23_13101
PubMedID: 36361897
Gene_locus related to this paper: mouse-Ces2c

Title : Rosiglitazone reverses inflammation in epididymal white adipose tissue in hormone-sensitive lipase-knockout mice - Kotzbeck_2022_J.Lipid.Res__100305
Author(s) : Kotzbeck P , Taschler U , Haudum C , Foessl I , Schoiswohl G , Boulgaropoulos B , Bounab K , Einsiedler J , Pajed L , Tilp A , Schwarz A , Eichmann TO , Obermayer-Pietsch B , Giordano A , Cinti S , Zechner R , Pieber TR
Ref : J Lipid Res , :100305 , 2022
Abstract : Hormone-sensitive lipase (HSL) plays a crucial role in intracellular lipolysis, and loss of HSL leads to diacylglycerol (DAG) accumulation, reduced fatty acid mobilization, and impaired peroxisome proliferator-activated receptor (PPAR) gamma signaling. HSL knock-out mice exhibit adipose tissue inflammation, but the underlying mechanisms are still not clear. Here we investigated if and to what extent HSL loss contributes to endoplasmic reticulum (ER) stress and adipose tissue inflammation in HSL knock-out mice. Further, we were interested in how impaired PPARgamma signaling affects the development of inflammation in epididymal white adipose tissue (eWAT) and inguinal white adipose tissue (iWAT) of HSL knock-out mice, and if DAG and ceramide (Cer) accumulation contribute to adipose tissue inflammation and ER stress. Ultrastructural analysis showed a markedly dilated ER in both eWAT and iWAT upon loss of HSL. In addition, HSL knock-out mice exhibited macrophage infiltration and increased F4/80 mRNA expression, a marker of macrophage activation, in eWAT, but not in iWAT. We show treatment with rosiglitazone, a PPARgamma agonist, attenuated macrophage infiltration and ameliorated inflammation of eWAT, but expression of ER stress markers remained unchanged, as did DAG and Cer levels in eWAT. Taken together, we show HSL loss promoted ER stress in both eWAT and iWAT of HSL knock-out mice, but inflammation and macrophage infiltration occurred mainly in eWAT. Also, PPARgamma activation reversed inflammation, but not ER stress and DAG accumulation. These data indicate that neither reduction of DAG levels nor ER stress contribute to the reversal of eWAT inflammation in HSL knock-out mice.
ESTHER : Kotzbeck_2022_J.Lipid.Res__100305
PubMedSearch : Kotzbeck_2022_J.Lipid.Res__100305
PubMedID: 36273647

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 : Carboxylesterase 2 proteins are efficient diglyceride and monoglyceride lipases possibly implicated in metabolic disease - Chalhoub_2021_J.Lipid.Res__100075
Author(s) : Chalhoub G , Kolleritsch S , Maresch LK , Taschler U , Pajed L , Tilp A , Natmessnig H , Rosina P , Kien B , Radner FPW , Schicho R , Oberer M , Schoiswohl G , Haemmerle G
Ref : J Lipid Res , :100075 , 2021
Abstract : Carboxylesterase 2 (CES2/Ces2) proteins exert established roles in (pro)drug metabolism. Recently, human and murine CES2/Ces2c have been discovered as triglyceride (TG) hydrolases implicated in the development of obesity and fatty liver disease. The murine Ces2 family consists of seven homologous genes as opposed to a single CES2 gene in humans. However, the mechanistic role of Ces2 protein family members is not completely understood. In this study, we examined activities of all Ces2 members towards TGs, diglycerides (DGs) and monoglycerides (MGs) as substrate. Besides CES2/Ces2c, we measured significant TG hydrolytic activities for Ces2a, Ces2b, and Ces2e. Notably, these Ces2 members and CES2 efficiently hydrolyzed DGs and MGs and their activities even surpassed those measured for TG hydrolysis. The localization of CES2/Ces2c proteins at the ER may implicate a role of these lipases in lipid signaling pathways. We found divergent expression of Ces2 genes in the liver and intestine of mice on high fat diet, which could relate to changes in lipid signaling. Finally, we demonstrate reduced CES2 expression in the colon of patients with inflammatory bowel disease and a similar decline in Ces2 expression in the colon of a murine colitis model. Together, these results demonstrate that CES2/Ces2 members are highly efficient DG and MG hydrolases that may play an important role in liver and gut lipid signaling.
ESTHER : Chalhoub_2021_J.Lipid.Res__100075
PubMedSearch : Chalhoub_2021_J.Lipid.Res__100075
PubMedID: 33872605
Gene_locus related to this paper: human-CES2 , mouse-Ces2a , mouse-Ces2b , mouse-Ces2c

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 : Hepatocyte-specific deletion of lysosomal acid lipase leads to cholesteryl ester but not triglyceride or retinyl ester accumulation - Pajed_2019_J.Biol.Chem_294_9118
Author(s) : Pajed L , Wagner C , Taschler U , Schreiber R , Kolleritsch S , Fawzy N , Pototschnig I , Schoiswohl G , Pusch LM , Wieser BI , Vesely P , Hoefler G , Eichmann TO , Zimmermann R , Lass A
Ref : Journal of Biological Chemistry , 294 :9118 , 2019
Abstract : Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester (CE) and retinyl ester (RE) and triglyceride (TG). Mice globally lacking LAL accumulate CE most prominently in the liver. The severity of the CE accumulation phenotype progresses with age and is accompanied by hepatomegaly and hepatic cholesterol crystal deposition. In contrast, hepatic TG accumulation is much less pronounced in these mice, and hepatic RE levels are even decreased. To dissect the functional role of LAL for neutral lipid ester mobilization in the liver, we generated mice specifically lacking LAL in hepatocytes (hep-LAL-ko). On a standard chow diet, hep-LAL-ko mice exhibited increased hepatic CE accumulation but unaltered TG and RE levels. Feeding the hep-LAL-ko mice a vitamin A excess/high-fat diet (VitA/HFD) further increased hepatic cholesterol levels, but hepatic TG and RE levels in these mice were lower than in control mice. Performing in vitro activity assays with lysosome-enriched fractions from livers of mice globally lacking LAL, we detected residual acid hydrolytic activities against TG and RE. Interestingly, this non-LAL acid TG hydrolytic activity was elevated in lysosome-enriched fractions from livers of hep-LAL-ko mice upon VitA/HFD feeding. In conclusion, the neutral lipid ester phenotype in livers from hep-LAL-ko mice indicates that LAL is limiting for CE turnover, but not for TG and RE turnovers. Furthermore, in vitro hydrolase activity assays revealed the existence of non-LAL acid hydrolytic activities for TG and RE. The corresponding acid lipase(s) catalyzing these reactions remains to be identified.
ESTHER : Pajed_2019_J.Biol.Chem_294_9118
PubMedSearch : Pajed_2019_J.Biol.Chem_294_9118
PubMedID: 31023823

Title : Intestine-Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet-Induced Liver Steatosis and Obesity - Maresch_2019_Hepatol.Commun_3_227
Author(s) : Maresch LK , Benedikt P , Feiler U , Eder S , Zierler KA , Taschler U , Kolleritsch S , Eichmann TO , Schoiswohl G , Leopold C , Wieser BI , Lackner C , Rulicke T , van Klinken J , Kratky D , Moustafa T , Hoefler G , Haemmerle G
Ref : Hepatol Commun , 3 :227 , 2019
Abstract : Murine hepatic carboxylesterase 2c (Ces2c) and the presumed human ortholog carboxylesterase 2 (CES2) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that Ces2c hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, Ces2c/CES2 is most abundantly expressed in the intestine, indicating a role of Ces2c/CES2 in intestinal TG metabolism. Here we show that Ces2c is an important enzyme in intestinal lipid metabolism in mice. Intestine-specific Ces2c overexpression (Ces2c(int)) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high-fat diet-fed Ces2c(int) mice were resistant to excessive diet-induced weight gain and adipose tissue expansion. Notably, intestinal Ces2c overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2c(int) mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that Ces2c is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re-esterification. Consequently, the increased availability of MGs and DGs for re-esterification and primordial apolipoprotein B48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. Conclusion: This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet-induced weight gain during metabolic stress.
ESTHER : Maresch_2019_Hepatol.Commun_3_227
PubMedSearch : Maresch_2019_Hepatol.Commun_3_227
PubMedID: 30766961
Gene_locus related to this paper: mouse-Ces2c

Title : Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance - Xia_2018_Cell.Rep_23_1948
Author(s) : Xia W , Pessentheiner AR , Hofer DC , Amor M , Schreiber R , Schoiswohl G , Eichmann TO , Walenta E , Itariu B , Prager G , Hackl H , Stulnig T , Kratky D , Rulicke T , Bogner-Strauss JG
Ref : Cell Rep , 23 :1948 , 2018
Abstract : Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that alpha/beta-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance.
ESTHER : Xia_2018_Cell.Rep_23_1948
PubMedSearch : Xia_2018_Cell.Rep_23_1948
PubMedID: 29768196
Gene_locus related to this paper: human-ABHD15 , mouse-ABH15

Title : Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase - Kumari_2012_Cell.Metab_15_691
Author(s) : Kumari M , Schoiswohl G , Chitraju C , Paar M , Cornaciu I , Rangrez AY , Wongsiriroj N , Nagy HM , Ivanova PT , Scott SA , Knittelfelder O , Rechberger GN , Birner-Gruenberger R , Eder S , Brown HA , Haemmerle G , Oberer M , Lass A , Kershaw EE , Zimmermann R , Zechner R
Ref : Cell Metab , 15 :691 , 2012
Abstract : Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.
ESTHER : Kumari_2012_Cell.Metab_15_691
PubMedSearch : Kumari_2012_Cell.Metab_15_691
PubMedID: 22560221

Title : The N-terminal region of comparative gene identification-58 (CGI-58) is important for lipid droplet binding and activation of adipose triglyceride lipase - Gruber_2010_J.Biol.Chem_285_12289
Author(s) : Gruber A , Cornaciu I , Lass A , Schweiger M , Poeschl M , Eder C , Kumari M , Schoiswohl G , Wolinski H , Kohlwein SD , Zechner R , Zimmermann R , Oberer M
Ref : Journal of Biological Chemistry , 285 :12289 , 2010
Abstract : In mammals, excess energy is stored in the form of triacylglycerol primarily in lipid droplets of white adipose tissue. The first step of lipolysis (i.e. the mobilization of fat stores) is catalyzed by adipose triglyceride lipase (ATGL). The enzymatic activity of ATGL is strongly enhanced by CGI-58 (comparative gene identification-58), and the loss of either ATGL or CGI-58 function causes systemic triglyceride accumulation in humans and mice. However, the mechanism by which CGI-58 stimulates ATGL activity is unknown. To gain insight into CGI-58 function using structural features of the protein, we generated a three-dimensional homology model based on sequence similarity with other proteins. Interestingly, the model of CGI-58 revealed that the N terminus forms an extension of the otherwise compact structure of the protein. This N-terminal region (amino acids 1-30) harbors a lipophilic tryptophan-rich stretch, which affects the localization of the protein. (1)H NMR experiments revealed strong interaction between the N-terminal peptide and dodecylphosphocholine micelles as a lipid droplet-mimicking system. A role for this N-terminal region of CGI-58 in lipid droplet binding was further strengthened by localization studies in cultured cells. Although wild-type CGI-58 localizes to the lipid droplet, the N-terminally truncated fragments of CGI-58 are dispersed in the cytoplasm. Moreover, CGI-58 lacking the N-terminal extension loses the ability to stimulate ATGL, implying that the ability of CGI-58 to activate ATGL is linked to correct localization. In summary, our study shows that the N-terminal, Trp-rich region of CGI-58 is essential for correct localization and ATGL-activating function of CGI-58.
ESTHER : Gruber_2010_J.Biol.Chem_285_12289
PubMedSearch : Gruber_2010_J.Biol.Chem_285_12289
PubMedID: 20164531

Title : Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58) - Radner_2010_J.Biol.Chem_285_7300
Author(s) : Radner FP , Streith IE , Schoiswohl G , Schweiger M , Kumari M , Eichmann TO , Rechberger G , Koefeler HC , Eder S , Schauer S , Theussl HC , Preiss-Landl K , Lass A , Zimmermann R , Hoefler G , Zechner R , Haemmerle G
Ref : Journal of Biological Chemistry , 285 :7300 , 2010
Abstract : Comparative gene identification-58 (CGI-58), also designated as alpha/beta-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58(-/-)) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58(-/-) mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGL-independent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58.
ESTHER : Radner_2010_J.Biol.Chem_285_7300
PubMedSearch : Radner_2010_J.Biol.Chem_285_7300
PubMedID: 20023287
Gene_locus related to this paper: mouse-abhd5

Title : Adipose triglyceride lipase plays a key role in the supply of the working muscle with fatty acids - Schoiswohl_2010_J.Lipid.Res_51_490
Author(s) : Schoiswohl G , Schweiger M , Schreiber R , Gorkiewicz G , Preiss-Landl K , Taschler U , Zierler KA , Radner FP , Eichmann TO , Kienesberger PC , Eder S , Lass A , Haemmerle G , Alsted TJ , Kiens B , Hoefler G , Zechner R , Zimmermann R
Ref : J Lipid Res , 51 :490 , 2010
Abstract : FAs are mobilized from triglyceride (TG) stores during exercise to supply the working muscle with energy. Mice deficient for adipose triglyceride lipase (ATGL-ko) exhibit defective lipolysis and accumulate TG in adipose tissue and muscle, suggesting that ATGL deficiency affects energy availability and substrate utilization in working muscle. In this study, we investigated the effect of moderate treadmill exercise on blood energy metabolites and liver glycogen stores in mice lacking ATGL. Because ATGL-ko mice exhibit massive accumulation of TG in the heart and cardiomyopathy, we also investigated a mouse model lacking ATGL in all tissues except cardiac muscle (ATGL-ko/CM). In contrast to ATGL-ko mice, these mice did not accumulate TG in the heart and had normal life expectancy. Exercise experiments revealed that ATGL-ko and ATGL-ko/CM mice are unable to increase circulating FA levels during exercise. The reduced availability of FA for energy conversion led to rapid depletion of liver glycogen stores and hypoglycemia. Together, our studies suggest that ATGL-ko mice cannot adjust circulating FA levels to the increased energy requirements of the working muscle, resulting in an increased use of carbohydrates for energy conversion. Thus, ATGL activity is required for proper energy supply of the skeletal muscle during exercise.
ESTHER : Schoiswohl_2010_J.Lipid.Res_51_490
PubMedSearch : Schoiswohl_2010_J.Lipid.Res_51_490
PubMedID: 19965578

Title : The C-terminal region of human adipose triglyceride lipase affects enzyme activity and lipid droplet binding - Schweiger_2008_J.Biol.Chem_283_17211
Author(s) : Schweiger M , Schoiswohl G , Lass A , Radner FP , Haemmerle G , Malli R , Graier W , Cornaciu I , Oberer M , Salvayre R , Fischer J , Zechner R , Zimmermann R
Ref : Journal of Biological Chemistry , 283 :17211 , 2008
Abstract : Adipose triglyceride lipase (ATGL) catalyzes the first step in the hydrolysis of triacylglycerol (TG) generating diacylglycerol and free fatty acids. The enzyme requires the activator protein CGI-58 (or ABHD5) for full enzymatic activity. Defective ATGL function causes a recessively inherited disorder named neutral lipid storage disease that is characterized by systemic TG accumulation and myopathy. In this study, we investigated the functional defects associated with mutations in the ATGL gene that cause neutral lipid storage disease. We show that these mutations lead to the expression of either inactive enzymes localizing to lipid droplets (LDs) or enzymatically active lipases with defective LD binding. Additionally, our studies assign important regulatory functions to the C-terminal part of ATGL. Truncated mutant ATGL variants lacking approximately 220 amino acids of the C-terminal protein region do not localize to LDs. Interestingly, however, these mutants exhibit substantially increased TG hydrolase activity in vitro (up to 20-fold) compared with the wild-type enzyme, indicating that the C-terminal region suppresses enzyme activity. Protein-protein interaction studies revealed an increased binding of truncated ATGL to CGI-58, suggesting that the C-terminal part interferes with CGI-58 interaction and enzyme activation. Compared with the human enzyme, the C-terminal region of mouse ATGL is much less effective in suppressing enzyme activity, implicating species-dependent differences in enzyme regulation. Together, our results demonstrate that the C-terminal region of ATGL is essential for proper localization of the enzyme and suppresses enzyme activity.
ESTHER : Schweiger_2008_J.Biol.Chem_283_17211
PubMedSearch : Schweiger_2008_J.Biol.Chem_283_17211
PubMedID: 18445597

Title : Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis - Reid_2008_J.Biol.Chem_283_13087
Author(s) : Reid BN , Ables GP , Otlivanchik OA , Schoiswohl G , Zechner R , Blaner WS , Goldberg IJ , Schwabe RF , Chua SC, Jr. , Huang LS
Ref : Journal of Biological Chemistry , 283 :13087 , 2008
Abstract : Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver triglycerides by 40-60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-beta-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in beta-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular triglycerides could be attributed to increases in beta-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity.
ESTHER : Reid_2008_J.Biol.Chem_283_13087
PubMedSearch : Reid_2008_J.Biol.Chem_283_13087
PubMedID: 18337240

Title : Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome - Lass_2006_Cell.Metab_3_309
Author(s) : Lass A , Zimmermann R , Haemmerle G , Riederer M , Schoiswohl G , Schweiger M , Kienesberger P , Strauss JG , Gorkiewicz G , Zechner R
Ref : Cell Metab , 3 :309 , 2006
Abstract : Adipose triglyceride lipase (ATGL) was recently identified as an important triacylglycerol (TG) hydrolase promoting the catabolism of stored fat in adipose and nonadipose tissues. We now demonstrate that efficient ATGL enzyme activity requires activation by CGI-58. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman Syndrome (CDS), a rare genetic disease where TG accumulates excessively in multiple tissues. CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. Alleles of CGI-58 carrying point mutations associated with CDS fail to activate ATGL. Moreover, CGI-58/ATGL coexpression attenuates lipid accumulation in COS-7 cells. Antisense RNA-mediated reduction of CGI-58 expression in 3T3-L1 adipocytes inhibits TG mobilization. Finally, expression of functional CGI-58 in CDS fibroblasts restores lipolysis and reverses the abnormal TG accumulation typical for CDS. These data establish an important biochemical function for CGI-58 in the lipolytic degradation of fat, implicating this lipolysis activator in the pathogenesis of CDS.
ESTHER : Lass_2006_Cell.Metab_3_309
PubMedSearch : Lass_2006_Cell.Metab_3_309
PubMedID: 16679289
Gene_locus related to this paper: human-ABHD5