Knittelfelder O

References (4)

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 : Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice - Schweiger_2017_Nat.Commun_8_14859
Author(s) : Schweiger M , Romauch M , Schreiber R , Grabner GF , Hutter S , Kotzbeck P , Benedikt P , Eichmann TO , Yamada S , Knittelfelder O , Diwoky C , Doler C , Mayer N , De Cecco W , Breinbauer R , Zimmermann R , Zechner R
Ref : Nat Commun , 8 :14859 , 2017
Abstract : Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.
ESTHER : Schweiger_2017_Nat.Commun_8_14859
PubMedSearch : Schweiger_2017_Nat.Commun_8_14859
PubMedID: 28327588

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 : 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