Fledelius C

References (7)

Title : Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL) - Mayer_2015_Bioorg.Med.Chem_23_2904
Author(s) : Mayer N , Schweiger M , Melcher MC , Fledelius C , Zechner R , Zimmermann R , Breinbauer R
Ref : Bioorganic & Medicinal Chemistry , 23 :2904 , 2015
Abstract : Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50=10muM in an assay with COS7-cell lysate overexpressing murine ATGL.
ESTHER : Mayer_2015_Bioorg.Med.Chem_23_2904
PubMedSearch : Mayer_2015_Bioorg.Med.Chem_23_2904
PubMedID: 25778769

Title : Contraction-induced lipolysis is not impaired by inhibition of hormone-sensitive lipase in skeletal muscle - Alsted_2013_J.Physiol_591_5141
Author(s) : Alsted TJ , Ploug T , Prats C , Serup AK , Hoeg L , Schjerling P , Holm C , Zimmermann R , Fledelius C , Galbo H , Kiens B
Ref : Journal of Physiology , 591 :5141 , 2013
Abstract : Abstract In skeletal muscle hormone-sensitive lipase (HSL) has long been accepted to be the principal enzyme responsible for lipolysis of intramyocellular triacylglycerol (IMTG) during contractions. However, this notion is based on in vitro lipase activity data, which may not reflect the in vivo lipolytic activity. We investigated lipolysis of IMTG in soleus muscles electrically stimulated to contract ex vivo during acute pharmacological inhibition of HSL in rat muscles and in muscles from HSL knockout (HSL-KO) mice. Measurements of IMTG are complicated by the presence of adipocytes located between the muscle fibres. To circumvent the problem with this contamination we analysed intramyocellular lipid droplet content histochemically. At maximal inhibition of HSL in rat muscles, contraction-induced breakdown of IMTG was identical to that seen in control muscles (P < 0.001). In response to contractions IMTG staining decreased significantly in both HSL-KO and WT muscles (P < 0.05). In vitro TG hydrolase activity data revealed that adipose triglyceride lipase (ATGL) and HSL collectively account for approximately 98% of the TG hydrolase activity in mouse skeletal muscle, other TG lipases accordingly being of negligible importance for lipolysis of IMTG. The present study is the first to demonstrate that contraction-induced lipolysis of IMTG occurs in the absence of HSL activity in rat and mouse skeletal muscle. Furthermore, the results suggest that ATGL is activated and plays a major role in lipolysis of IMTG during muscle contractions.
ESTHER : Alsted_2013_J.Physiol_591_5141
PubMedSearch : Alsted_2013_J.Physiol_591_5141
PubMedID: 23878361

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 : The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages - Igarashi_2010_Circ.Res_107_1387
Author(s) : Igarashi M , Osuga J , Uozaki H , Sekiya M , Nagashima S , Takahashi M , Takase S , Takanashi M , Li Y , Ohta K , Kumagai M , Nishi M , Hosokawa M , Fledelius C , Jacobsen P , Yagyu H , Fukayama M , Nagai R , Kadowaki T , Ohashi K , Ishibashi S
Ref : Circulation Research , 107 :1387 , 2010
Abstract : RATIONALE: Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis. OBJECTIVE: We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis. METHODS AND RESULTS: We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions. CONCLUSIONS: NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis.
ESTHER : Igarashi_2010_Circ.Res_107_1387
PubMedSearch : Igarashi_2010_Circ.Res_107_1387
PubMedID: 20947831

Title : Adipose triglyceride lipase in human skeletal muscle is upregulated by exercise training - Alsted_2009_Am.J.Physiol.Endocrinol.Metab_296_E445
Author(s) : Alsted TJ , Nybo L , Schweiger M , Fledelius C , Jacobsen P , Zimmermann R , Zechner R , Kiens B
Ref : American Journal of Physiology Endocrinol Metab , 296 :E445 , 2009
Abstract : Mobilization of fatty acids from stored triacylglycerol (TG) in adipose tissue and skeletal muscle [intramyocellular triacylglycerol (IMTG)] requires activity of lipases. Although exercise training increases the lipolytic capacity of skeletal muscle, the expression of hormone-sensitive lipase (HSL) is not changed. Recently, adipose triglyceride lipase (ATGL) was identified as a TG-specific lipase in various rodent tissues. To investigate whether human skeletal muscle ATGL protein is regulated by endurance exercise training, 10 healthy young men completed 8 wk of supervised endurance exercise training. Western blotting analysis on lysates of skeletal muscle biopsy samples revealed that exercise training induced a twofold increase in skeletal muscle ATGL protein content. In contrast to ATGL, expression of comparative gene identification 58 (CGI-58), the activating protein of ATGL, and HSL protein was not significantly changed after the training period. The IMTG concentration was significantly decreased by 28% at termination of the training program compared with before. HSL-phoshorylation at Ser(660) was increased, HSL-Ser(659) phosporylation was unchanged, and HSL-phoshorylation at Ser(565) was decreased altogether, indicating an enhanced basal activity of this lipase. No change was found in the expression of diacylglycerol acyl transferase 1 (DGAT1) after training. Inhibition of HSL with a monospecific, small molecule inhibitor (76-0079) and stimulation of ATGL with CGI-58 revealed that significant ATGL activity is present in human skeletal muscle. These results suggest that ATGL in addition to HSL may be important for human skeletal muscle lipolysis.
ESTHER : Alsted_2009_Am.J.Physiol.Endocrinol.Metab_296_E445
PubMedSearch : Alsted_2009_Am.J.Physiol.Endocrinol.Metab_296_E445
PubMedID: 19106247

Title : Synthesis and structure-activity relationship for a novel class of potent and selective carbamate-based inhibitors of hormone selective lipase with acute in vivo antilipolytic effects - Ebdrup_2007_J.Med.Chem_50_5449
Author(s) : Ebdrup S , Refsgaard HH , Fledelius C , Jacobsen P
Ref : Journal of Medicinal Chemistry , 50 :5449 , 2007
Abstract : Hormone-sensitive lipase (HSL) is an intracellular enzyme that has a central role in the regulation of fatty acid metabolism. The enzyme, therefore, is a potentially interesting pharmacological target for the treatment of insulin resistance and dyslipidemic disorders. Based on a high throughput screening, a carbamate based HSL inhibitor was identified and optimized into the selective HSL inhibitors 4-hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13f) and 4-hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13g), with IC50 values of 110 and 500 nM, respectively. Both inhibitors were active in acute antilipolytic experiments in vivo and none of the inhibitors inhibited the cytochrome P450 (CYP) isoforms 2D6, 3A4, and 1A2.
ESTHER : Ebdrup_2007_J.Med.Chem_50_5449
PubMedSearch : Ebdrup_2007_J.Med.Chem_50_5449
PubMedID: 17918819

Title : Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism - Schweiger_2006_J.Biol.Chem_281_40236
Author(s) : Schweiger M , Schreiber R , Haemmerle G , Lass A , Fledelius C , Jacobsen P , Tornqvist H , Zechner R , Zimmermann R
Ref : Journal of Biological Chemistry , 281 :40236 , 2006
Abstract : The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis.
ESTHER : Schweiger_2006_J.Biol.Chem_281_40236
PubMedSearch : Schweiger_2006_J.Biol.Chem_281_40236
PubMedID: 17074755