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Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences. Tallinn University of Technology, Department of Chemistry, Tallinn, Estonia.
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2014 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 450, no 2, 1063-1069 p.Article in journal (Refereed) Published
Abstract [en]

Patients at increased cardiovascular risk commonly display high levels of plasma triglycerides (TGs) levels, elevated LDL cholesterol, small dense LDL particles and low levels of HDL-cholesterol. Many remain at high risk even after successful statin therapy, presumably because TG levels remain high. Lipoprotein lipase (LPL) maintains TG homeostasis in blood by hydrolysis of TG-rich lipoproteins. Efficient clearance of TGs is accompanied by increased levels of HDL-cholesterol and decreased levels of small dense LDL. Given the central role of LPL in lipid metabolism we sought to find small molecules that could increase LPL activity and serve as starting points for drug development efforts against cardiovascular disease. Using a small molecule screening approach we have identified small molecules that can protect LPL from inactivation by the controller protein angiopoietin-like protein 4 during incubations in vitro. One of the selected compounds, 50F10, was directly shown to preserve the active homodimer structure of LPL, as demonstrated by heparin-Sepharose chromatography. This compound tended to reduce fasting TG levels in normal rats. On injection to hypertriglyceridemic apolipoprotein A-V deficient mice the compound ameliorated the postprandial response after an olive oil gavage. This compound is a potential lead compound for the development of drugs that could reduce the residual risk associated with elevated TGs in dyslipidemia.

Place, publisher, year, edition, pages
Elsevier, 2014. Vol. 450, no 2, 1063-1069 p.
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-91689DOI: 10.1016/j.bbrc.2014.06.114OAI: oai:DiVA.org:umu-91689DiVA: diva2:737688
Funder
Swedish Research CouncilVinnovaKnut and Alice Wallenberg FoundationCarl Tryggers foundation
Available from: 2014-08-13 Created: 2014-08-13 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Endogenous and exogenous factors affecting lipoprotein lipase activity
Open this publication in new window or tab >>Endogenous and exogenous factors affecting lipoprotein lipase activity
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Individuals with high levels of plasma triglycerides are at high risk to develop cardiovascular disease (CVD), currently one of the major causes of death worldwide. Recent epidemiological studies show that loss-of-function mutations in the APOC3 gene lower plasma triglyceride levels and reduce the incidence of coronary artery disease. The APOC3 gene encodes for apolipoprotein (APO) C3, known as an inhibitor of lipoprotein lipase (LPL) activity. Similarly, a common gain-of-function mutation in the LPL gene is associated with reduced risk for CVD.

LPL is central for the metabolism of lipids in blood. The enzyme acts at the endothelial surface of the capillary bed where it hydrolyzes triglycerides in circulating triglyceride-rich lipoproteins (TRLs) and thereby allows uptake of fatty acids in adjacent tissues. LPL activity has to be rapidly modulated to adapt to the metabolic demands of different tissues. The current view is that LPL is constitutively expressed and that the rapid modulation of the enzymatic activity occurs by some different controller proteins. Angiopoietin-like protein 4 (ANGPTL4) is one of the main candidates for control of LPL activity. ANGPTL4 causes irreversible inactivation through dissociation of the active LPL dimer to inactive monomers. Other proteins that have effects on LPL activity are the APOCs which are surface components of the substrate TRLs. APOC2 is a well-known LPL co-factor, whereas APOC1 and APOC3 independently inhibit LPL activity.

Given the important role of LPL for triglyceride homeostasis in blood, the aim of this thesis was to find small molecules that could increase LPL activity and serve as lead compounds in future drug discovery efforts. Another aim was to investigate the molecular mechanisms for how APOC1 and APOC3 inhibit LPL activity.

Using a small molecule screening library we have identified small molecules that can protect LPL from inactivation by ANGPTL4 during incubations in vitro. Following a structure-activity relationship study we have synthesized lead compounds that more efficiently protect LPL from inactivation by ANGPTL4 in vitro and also have dramatic triglyceride-lowering properties in vivo. In a separate study we show that low concentrations of fatty acids possess the ability to prevent inactivation of LPL by ANGPTL4 under in vitro conditions.

With regard to APOC1 and APOC3 we demonstrate that when bound to TRLs, these apolipoproteins prevent binding of LPL to the lipid/water interface. This results in decreased lipolysis and in an increased susceptibility of LPL to inactivation by ANGPTL4. We demonstrate that hydrophobic amino acid residues that are centrally located in the APOC3 molecule are critical for attachment of this protein to lipid emulsion particles and consequently for inhibition of LPL activity.

In summary, this work has identified a lead compound that protects LPL from inactivation by ANGPTL4 in vitro and lowers triglycerides in vivo. In addition, we propose a molecular mechanism for inhibition of LPL activity by APOC1 and APOC3.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2014. 56 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1669
Keyword
LPL, APOC1, APOC2, APOC3, ANGPTL4, enzyme inactivation, lipoprotein metabolism, triglycerides, fatty acids, hypertriglyceridemia, CVD, small molecule screening, structure-activity relationship
National Category
Cell and Molecular Biology
Research subject
Medicine, cardiovascular disease
Identifiers
urn:nbn:se:umu:diva-91662 (URN)978-91-7601-115-7 (ISBN)
Public defence
2014-08-27, NUS - Norrlands universitetssjukhus, Sal E04, Byggnad 6E, Umeå Universitet, Umeå, 14:00 (English)
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Available from: 2014-08-15 Created: 2014-08-13 Last updated: 2014-08-14Bibliographically approved

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