Maresch LK

References (3)

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 : Intestine-Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet-Induced Liver Steatosis and Obesity - Maresch_2019_Hepatol.Commun_3_227
Author(s) : Maresch LK , Benedikt P , Feiler U , Eder S , Zierler KA , Taschler U , Kolleritsch S , Eichmann TO , Schoiswohl G , Leopold C , Wieser BI , Lackner C , Rulicke T , van Klinken J , Kratky D , Moustafa T , Hoefler G , Haemmerle G
Ref : Hepatol Commun , 3 :227 , 2019
Abstract : Murine hepatic carboxylesterase 2c (Ces2c) and the presumed human ortholog carboxylesterase 2 (CES2) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that Ces2c hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, Ces2c/CES2 is most abundantly expressed in the intestine, indicating a role of Ces2c/CES2 in intestinal TG metabolism. Here we show that Ces2c is an important enzyme in intestinal lipid metabolism in mice. Intestine-specific Ces2c overexpression (Ces2c(int)) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high-fat diet-fed Ces2c(int) mice were resistant to excessive diet-induced weight gain and adipose tissue expansion. Notably, intestinal Ces2c overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2c(int) mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that Ces2c is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re-esterification. Consequently, the increased availability of MGs and DGs for re-esterification and primordial apolipoprotein B48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. Conclusion: This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet-induced weight gain during metabolic stress.
ESTHER : Maresch_2019_Hepatol.Commun_3_227
PubMedSearch : Maresch_2019_Hepatol.Commun_3_227
PubMedID: 30766961
Gene_locus related to this paper: mouse-Ces2c

Title : Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation - Leopold_2019_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1864_500
Author(s) : Leopold C , Duta-Mare M , Sachdev V , Goeritzer M , Maresch LK , Kolb D , Reicher H , Wagner B , Stojakovic T , Ruelicke T , Haemmerle G , Hoefler G , Sattler W , Kratky D
Ref : Biochimica & Biophysica Acta Molecular & Cellular Biology Lipids , 1864 :500 , 2019
Abstract : Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa(-/-)) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa(-/-) mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa(-/-) mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa(-/-) mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability.
ESTHER : Leopold_2019_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1864_500
PubMedSearch : Leopold_2019_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids_1864_500
PubMedID: 30639734
Gene_locus related to this paper: mouse-1llip