Showing papers on "Endothelial lipase published in 2018"
TL;DR: Notch signaling is identified as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart, implying that the endothelialium controls cardiomyocyte metabolism and function.
Abstract: Background: Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. Methods: Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. Results: Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ–mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ–deficient mice. Conclusions: This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.
95 citations
TL;DR: The role of LIPG in lipid metabolism and the inflammatory response is focused on, and the recent insights in its involvement in tumor progression are highlighted.
Abstract: Endothelial lipase (LIPG) plays a critical role in lipoprotein metabolism, cytokine expression, and the lipid composition of cells. Thus far, the extensive investigations of LIPG have focused on its mechanisms and involvement in metabolic syndromes such as atherosclerosis. However, recent developments have found that LIPG plays a role in cancer. This review summarizes the field of LIPG study. We focus on the role of LIPG in lipid metabolism and the inflammatory response, and highlight the recent insights in its involvement in tumor progression. Finally, we discuss the potential of targeting LIPG in therapeutic strategies.
40 citations
TL;DR: Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo.
Abstract: Objective— Reverse cholesterol transport (RCT) is a major mechanism by which HDL (high-density lipoprotein) protects against atherosclerosis. Endothelial lipase (EL) reportedly reduces HDL levels, which, in theory, would increase atherosclerosis. However, it remains unclear whether EL affects RCT in vivo. Approach and Results— Adenoviral vectors expressing EL or luciferase were intravenously injected into mice, and a macrophage RCT assay was performed. As expected, hepatic EL overexpression markedly reduced HDL levels. In parallel, plasma 3 H-cholesterol counts from the EL-expressing mice decreased by 85% compared with control. Surprisingly, there was no difference in fecal 3 H-cholesterol excretion between the groups. Kinetic studies revealed increased catabolism/hepatic uptake of 3 HDL-cholesteryl ether, resulting in no change in fecal HDL-cholesteryl ester excretion in the mice. To explore underlying mechanisms for the preservation of RCT despite low HDL levels in the EL-expressing mice, we investigated the effects of hepatic SR-BI (scavenger receptor class B type I) knockdown. RCT assay revealed that knockdown of SR-BI alone reduced fecal excretion of macrophage-derived 3 H-cholesterol. Interestingly, hepatic EL overexpression under SR-BI inhibition further attenuated fecal tracer counts as compared with control. Finally, we observed that EL overexpression enhanced in vivo RCT under pharmacological inhibition of hepatic ABCA1 (ATP-binding cassette transporter A1) by probucol. Conclusions— Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo. In contrast, EL-modified HDL might negatively regulate RCT via hepatic ABCA1. Despite extreme hypoalphalipoproteinemia, RCT is maintained in EL-expressing mice via SR-BI/ABCA1-dependent pathways.
24 citations
TL;DR: The endothelial lipase gene (584 C/T) T allele might be protective in association with coronary artery disease and is related to risk for CAD in the Turkish population probably through altering HDL-C metabolism.
Abstract: Background/aim The endothelial lipase gene (LIPG) has a major role in regulating high density lipoprotein cholesterol (HDL-C), therefore this study investigated whether LIPG is associated with coronary artery disease (CAD) in a Turkish population. Materials and methods The LIPG (584 C/T) mutation was analyzed in 74 CAD patients and 73 controls. Results There was a significant difference between the two groups regarding the mutant T allele frequencies (χ2=0.456, p=0.020; 26.7% and 41.8% in patient and control groups, respectively) for 584 C/T. Even though the TT genotype was not significantly different, it had p=0.054 which supported our results. Conclusion The endothelial lipase gene (584 C/T) T allele might be protective in association with coronary artery disease. Therefore, LIPG gene is related to risk for CAD in the Turkish population probably through altering HDL-C metabolism.
8 citations
TL;DR: Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.
Abstract: Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.
7 citations
TL;DR: In heart and AT, no differences were found in Lipg mRNA between groups, while AT Lpl mRNA and LPL protein were decreased in HFD, without differences in heart, and the increase in EL activity could be an alternative pathway for fatty acid release from lipoproteins and uptake in tissues with decreased LPL activity.
Abstract: Lipoprotein lipase (LPL) and endothelial lipase (EL) are involved in lipoprotein metabolism. In insulin-resistance, their behavior is altered. Peroxisome proliferator-activated receptors (PPAR) and apoproteins (apo)CII and CIII could be partly responsible for these alterations. To evaluate this response, we assessed Lpl and Lipg expression, protein levels, and enzyme activity in adipose tissue (AT) and heart in an obesity model. Besides, we assessed the role of PPAR and apoC. Male Wistar rats were fed with standard diet (Control, n = 14) or high-fat diet (HFD, n = 14) for 14 weeks. Glucose and lipoprotein profiles were measured. Histological studies were performed in heart and epididymal AT. Lpl and Lipg were assessed by reverse transcription polymerase chain reaction (RT-qPCR), protein levels by Western Blot, and activities by radiometric assays. Cardiac and AT PPAR expression were measured by Western Blot and hepatic Apoc2 and Apoc3 mRNA by RT-qPCR. In HFD, fat deposits were observed in hearts, whereas AT presented a higher adipocyte size. In heart and AT, no differences were found in Lipg mRNA between groups, while AT Lpl mRNA and LPL protein were decreased in HFD, without differences in heart. In both tissues, EL protein levels and activity were increased and inversely associated with decreased LPL activity, being partially responsible for the atherogenic lipoprotein profile in HFD. PPARγ expression in AT was decreased in HFD, without differences in cardiac PPARδ expression and hepatic apoC mRNA. The increase in EL activity could be an alternative pathway for fatty acid release from lipoproteins and uptake in tissues with decreased LPL activity. In AT, PPARγ could be involved in enzyme regulation.
6 citations
TL;DR: The introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL is described, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
Abstract: Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
4 citations
TL;DR: Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides, several compounds were advanced to PK evaluation.
2 citations
25 Jul 2018
TL;DR: It is very relevant and expedient to study the various aspects of the use of EL to diagnose NAFLD and determe treatment strategy in patients with NAFLd and hypertension.
Abstract: ENDOTHELIAL LIPASE AS NEW DIAGNOSTIC MARKER OF NON-ALCOHOLIC FATTY LIVER DISEASE IN HYPERTENSIVE SUBJECTS (review)Bashkirova A.DNon-alcoholic fatty liver disease (NAFLD) and hypertension are among the most common diseases in the world. One of the negative factors contributing to the formation of cardiovascular risk in patients with NAFLD affected with hypertension is the low level of HDL cholesterol in which metabolism endothelial lipase (EL) plays a leading role. Therefore, it is very relevant and expedient to study the various aspects of the use of EL to diagnose NAFLD and determe treatment strategy in patients with NAFLD and hypertension.Key words: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, endothelial lipase, lipid metabolism, overweight. ЕНДОТЕЛІАЛЬНА ЛІПАЗА ЯК НОВИЙ ДІАГНОСТИЧНИЙ МАРКЕР НЕАЛКОГОЛЬНИЙ ЖИРОВОЇ ХВОРОБИ ПЕЧІНКИ (НАЖХП) У ОСІБ З ГІПЕРТЕНЗІЄЮ (огляд)Башкірова А.Д.НАЖХП і гіпертонічна хвороба є одними з найпоширеніших хвороб у світі. Одним з несприятливих факторів, що сприяють формуванню кардіоваскулярного ризику у пацієнтів з НАЖБП на тлі гіпертонічної хвороби, є низький рівень холестерину ЛПВЩ, в метаболізмі якого грає провідну роль активність ендотеліальної ліпази. Тому досить актуальним і доцільним є вивчення різних аспектів використання ЕЛ для діагностики НАЖБП з подальшим визначенням лікувальної тактики у хворих НАЖХП на тлі ГХ.Ключові слова: неалкогольна жирова хвороба печінки, неалкогольний стеатогепатит, гіпертонічна хвороба, ендотеліальналіпаза, ліпіднийобмін, надлишковамасатіла . ЭНДОТЕЛИАЛЬНАЯ ЛИПАЗА КАК НОВЫЙ ДИАГНОСТИЧЕСКИЙ МАРКЕР НЕАЛКОГОЛЬНОЙ ЖИРОВОЙ БОЛЕЗНИ ПЕЧЕНИ (НАЖБП)У ЛИЦ С ГИПЕРТЕНЗИЕЙ (обзор)Башкирова А.Д.НАЖБП и гипертоническая болезнь являются одними из самых распространенных болезней в мире. Одним из неблагоприятных факторов, способствующих формированию кардиоваскулярного риска у пациентов с НАЖБП на фоне гипертонической болезни, является низкий уровень холестерина ЛПВП, в метаболизме которого играет ведущую роль активность эндотелиальной липазы. Поэтому весьма актуальным и целесообразным является изучение различных аспектов использования ЭЛ для диагностики НАЖБП с последующим определением лечебной тактики у больных НАЖБП на фоне ГБ. Ключевые слова: неалкогольная жировая болезнь печени, неалкогольный стеатогепатит, гипертоническая болезнь, эндотелиальная липаза, липидный обмен, избыточная масса тела.