Pajed L

References (7)

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 : 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 : 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 : Lysosomal acid lipase is the major acid retinyl ester hydrolase in cultured human hepatic stellate cells but not essential for retinyl ester degradation - Wagner_2020_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1865_158730
Author(s) : Wagner C , Hois V , Pajed L , Pusch LM , Wolinski H , Trauner M , Zimmermann R , Taschler U , Lass A
Ref : Biochimica & Biophysica Acta Molecular & Cellular Biology Lipids , 1865 :158730 , 2020
Abstract : Vitamin A is stored as retinyl esters (REs) in lipid droplets of hepatic stellate cells (HSCs). To date, two different pathways are known to facilitate the breakdown of REs: (i) Hydrolysis of REs by neutral lipases, and (ii) whole lipid droplet degradation in autolysosomes by acid hydrolysis. In this study, we evaluated the contribution of neutral and acid RE hydrolases to the breakdown of REs in human HSCs. (R)-Bromoenol lactone (R-BEL), inhibitor of adipose triglyceride lipase (ATGL) and patatin-like phospholipase domain-containing 3 (PNPLA3), the hormone-sensitive lipase (HSL) inhibitor 76-0079, as well as the serine-hydrolase inhibitor Orlistat reduced neutral RE hydrolase activity of LX-2 cell-lysates between 20 and 50%. Interestingly, in pulse-chase experiments, R-BEL, 76-0079, as well as Orlistat exerted little to no effect on cellular RE breakdown of LX-2 cells as well as primary human HSCs. In contrast, Lalistat2, a specific lysosomal acid lipase (LAL) inhibitor, virtually blunted acid in vitro RE hydrolase activity of LX-2 cells. Accordingly, HSCs isolated from LAL-deficient mice showed RE accumulation and were virtually devoid of acidic RE hydrolase activity. In pulse-chase experiments however, LAL-deficient HSCs, similar to LX-2 cells and primary human HSCs, were not defective in degrading REs. In summary, results demonstrate that ATGL, PNPLA3, and HSL contribute to neutral RE hydrolysis of human HSCs. LAL is the major acid RE hydrolase in HSCs. Yet, LAL is not limiting for RE degradation under serum-starvation. Together, results suggest that RE breakdown of HSCs is facilitated by (a) so far unknown, non-Orlistat inhibitable RE-hydrolase(s).
ESTHER : Wagner_2020_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1865_158730
PubMedSearch : Wagner_2020_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1865_158730
PubMedID: 32361002
Gene_locus related to this paper: human-LIPA

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 : ATGL and CGI-58 are lipid droplet proteins of the hepatic stellate cell line HSC-T6 - Eichmann_2015_J.Lipid.Res_56_1972
Author(s) : Eichmann TO , Grumet L , Taschler U , Hartler J , Heier C , Woblistin A , Pajed L , Kollroser M , Rechberger G , Thallinger GG , Zechner R , Haemmerle G , Zimmermann R , Lass A
Ref : J Lipid Res , 56 :1972 , 2015
Abstract : Lipid droplets (LDs) of hepatic stellate cells (HSCs) contain large amounts of vitamin A [in the form of retinyl esters (REs)] as well as other neutral lipids such as TGs. During times of insufficient vitamin A availability, RE stores are mobilized to ensure a constant supply to the body. To date, little is known about the enzymes responsible for the hydrolysis of neutral lipid esters, in particular of REs, in HSCs. In this study, we aimed to identify LD-associated neutral lipid hydrolases by a proteomic approach using the rat stellate cell line HSC-T6. First, we loaded cells with retinol and FAs to promote lipid synthesis and deposition within LDs. Then, LDs were isolated and lipid composition and the LD proteome were analyzed. Among other proteins, we found perilipin 2, adipose TG lipase (ATGL), and comparative gene identification-58 (CGI-58), known and established LD proteins. Bioinformatic search of the LD proteome for alpha/beta-hydrolase fold-containing proteins revealed no yet uncharacterized neutral lipid hydrolases. In in vitro activity assays, we show that rat (r)ATGL, coactivated by rat (r)CGI-58, efficiently hydrolyzes TGs and REs. These findings suggest that rATGL and rCGI-58 are LD-resident proteins in HSCs and participate in the mobilization of both REs and TGs.
ESTHER : Eichmann_2015_J.Lipid.Res_56_1972
PubMedSearch : Eichmann_2015_J.Lipid.Res_56_1972
PubMedID: 26330055
Gene_locus related to this paper: human-ABHD5