Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Current Atherosclerosis Reports (Impact Factor: 3.42). 03/2011; 13(3):257-65. DOI: 10.1007/s11883-011-0175-2
Source: PubMed


Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.

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Available from: Wijtske Annema, Oct 04, 2015
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    • "Although the effect of EL inhibition in the reduction of atherosclerotic cardiovascular disease risk has not been proven (Yasuda et al. 2010; Annema and Tietge 2011), EL remains a potential target for pharmacological inhibition, possibly by antibodies against EL, as a novel strategy to raise HDL-C and reduce the risk of cardiovascular disease. "
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    ABSTRACT: The specificity of Watson-Crick base pairing and the development of several chemical modifications to oligonucleotides have enabled the development of novel drug classes for the treatment of different human diseases. This review focuses on promising results of recent preclinical or clinical studies on targeting HDL metabolism and function by antisense oligonucleotides and miRNA-based therapies. Although many hurdles regarding basic mechanism of action, delivery, specificity, and toxicity need to be overcome, promising results from recent clinical trials and recent approval of these types of therapy to treat dyslipidemia suggest that the treatment of HDL dysfunction will benefit from these unique clinical opportunities. Moreover, an overview of monoclonal antibodies (mAbs) developed for the treatment of dyslipidemia and cardiovascular disease and currently being tested in clinical studies is provided. Initial studies have shown that these compounds are generally safe and well tolerated, but ongoing large clinical studies will assess their long-term safety and efficacy.
    Handbook of experimental pharmacology 01/2015; 224:649-89. DOI:10.1007/978-3-319-09665-0_22
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    • "EL was discovered in 1999 as part of the triglyceride lipase family of genes [20]. EL has an essential phospholipase activity and is a critical enzyme in HDL metabolism [35]. The plasma HDL concentration is significantly increased in EL gene knockout mice and EL overexpression markedly reduces HDL plasma levels, which is an independent risk factor for atherosclerosis [36]. "
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    ABSTRACT: Background Angiotensin II (AngII) participates in endothelial damage and inflammation, and accelerates atherosclerosis. Endothelial lipase (EL) is involved in the metabolism and clearance of high density lipoproteins (HDL), the serum levels of which correlate negatively with the onset of cardiovascular diseases including atherosclerosis. However, the relationship between AngII and EL is not yet fully understood. In this study, we investigated the effects of AngII on the expression of EL and the signaling pathways that mediate its effects in human umbilical vein endothelial cells (HUVECs). Methods and Findings HUVECs were cultured in vitro with different treatments as follows: 1) The control group without any treatment; 2) AngII treatment for 0 h, 4 h, 8 h, 12 h and 24 h; 3) NF-κB activation inhibitor pyrrolidine dithiocarbamate (PDTC) pretreatment for 1 h before AngII treatment; and 4) mitogen-activated protein kinase (MAPK) p38 inhibitor (SB203580) pretreatment for 1 h before AngII treatment. EL levels in each group were detected by immunocytochemical staining and western blotting. HUVECs proliferation was detected by MTT and proliferating cell nuclear antigen (PCNA) immunofluorescence staining. NF-kappa B (NF-κB) p65, MAPK p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and phosphorylated extracellular signal-regulated kinase (p-ERK) expression levels were assayed by western blotting. The results showed that the protein levels of EL, NF-κB p65, MAPK p38, JNK, and p-ERK protein levels, in addition to the proliferation of HUVECs, were increased by AngII. Both the NF-kB inhibitor (PDTC) and the MAPK p38 inhibitor (SB203580) partially inhibited the effects of AngII on EL expression. Conclusion AngII may upregulate EL protein expression via the NF-κB and MAPK signaling pathways.
    PLoS ONE 09/2014; 9(9):e107634. DOI:10.1371/journal.pone.0107634 · 3.23 Impact Factor
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    • "In conclusion, it is clear that lipases are key players in the modulation of reverse cholesterol transport from macrophages [24] [26]. They exert their effect on the expression and function of the cholesterol transporter ABCA1, as well as on modifying the extracellular cholesterol acceptors: nascent HDL or lipid-poor apoAI. "
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    ABSTRACT: The ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of excess cholesterol from foam cells to lipid-poor apolipoprotein A-I, in a process called reverse cholesterol transport. Lipoprotein lipase (LPL) is a lipolytic enzyme expressed by macrophages within atherosclerotic lesions. Lentivirus-mediated RNA interference was used to genetically knock-down (KD) the expression of LPL in THP-1 macrophages. Silencing of the LPL gene was confirmed by end-point PCR, real time PCR, and protein analysis. Suppression of LPL expression correlated with a 1.6-fold up-regulation of ABCA1 mRNA levels, and resulted in a 4.5-fold increase in ABCA1-dependent cholesterol efflux. Replenishing LPL by addition of purified bovine LPL to the cell culture media resulted in down-regulation of ABCA1-mediated cholesterol efflux in both wild-type and LPL knockdown cells. These finding suggests an inverse correlation between macrophage LPL levels and ABCA1 cholesterol transport activity.
    Biochemical and Biophysical Research Communications 07/2014; 450(4). DOI:10.1016/j.bbrc.2014.07.015 · 2.30 Impact Factor
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