Radner FPW

References (5)

Title : Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes - Grabner_2022_J.Am.Chem.Soc__
Author(s) : Grabner GF , Guttenberger N , Mayer N , Migglautsch-Sulzer AK , Lembacher-Fadum C , Fawzy N , Bulfon D , Hofer P , Zullig T , Hartig L , Kulminskaya N , Chalhoub G , Schratter M , Radner FPW , Preiss-Landl K , Masser S , Lass A , Zechner R , Gruber K , Oberer M , Breinbauer R , Zimmermann R
Ref : Journal of the American Chemical Society , : , 2022
Abstract : Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme-inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.
ESTHER : Grabner_2022_J.Am.Chem.Soc__
PubMedSearch : Grabner_2022_J.Am.Chem.Soc__
PubMedID: 35362954

Title : ABHD5-A Regulator of Lipid Metabolism Essential for Diverse Cellular Functions - Schratter_2022_Metabolites_12_1015
Author(s) : Schratter M , Lass A , Radner FPW
Ref : Metabolites , 12 :1015 , 2022
Abstract : The alpha/beta-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.
ESTHER : Schratter_2022_Metabolites_12_1015
PubMedSearch : Schratter_2022_Metabolites_12_1015
PubMedID: 36355098
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

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 : Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides - Brejchova_2021_Proc.Natl.Acad.Sci.U.S.A_118_
Author(s) : Brejchova K , Radner FPW , Balas L , Paluchova V , Cajka T , Chodounska H , Kudova E , Schratter M , Schreiber R , Durand T , Zechner R , Kuda O
Ref : Proc Natl Acad Sci U S A , 118 : , 2021
Abstract : Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.
ESTHER : Brejchova_2021_Proc.Natl.Acad.Sci.U.S.A_118_
PubMedSearch : Brejchova_2021_Proc.Natl.Acad.Sci.U.S.A_118_
PubMedID: 33372146

Title : ABHD5 stimulates PNPLA1-mediated omega-O-acylceramide biosynthesis essential for a functional skin permeability barrier - Kien_2018_J.Lipid.Res_59_2360
Author(s) : Kien B , Grond S , Haemmerle G , Lass A , Eichmann TO , Radner FPW
Ref : J Lipid Res , 59 :2360 , 2018
Abstract : Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and alpha/beta-hydrolase domain-containing 5 (ABHD5), also known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Individuals with mutations in either of these genes show a defect in epidermal omega-O-acylceramide (AcylCer) biosynthesis, suggesting that PNPLA1 and ABHD5 act in the same metabolic pathway. In this report, we identified ABHD5 as a coactivator of PNPLA1 that stimulates the esterification of omega-hydroxy ceramides with linoleic acid for AcylCer biosynthesis. ABHD5 interacts with PNPLA1 and recruits the enzyme to its putative triacylglycerol substrate onto cytosolic lipid droplets. Conversely, alleles of ABHD5 carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis. Our findings establish an important biochemical function of ABHD5 in interacting with PNPLA1 to synthesize crucial epidermal lipids, emphasizing the significance of these proteins in the formation of a functional skin permeability barrier.
ESTHER : Kien_2018_J.Lipid.Res_59_2360
PubMedSearch : Kien_2018_J.Lipid.Res_59_2360
PubMedID: 30361410
Gene_locus related to this paper: human-ABHD5