Mrak I

References (3)

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 : 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