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Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 47, 33997-34008 p.Article in journal (Refereed) Published
Abstract [en]

Apolipoproteins (apo) C-I and C-III are known to inhibit lipoprotein lipase (LPL) activity, but the molecular mechanisms for this remain obscure. We present evidence that either apoC-I or apoC-III, when bound to triglyceride-rich lipoproteins, prevent binding of LPL to the lipid/water interface. This results in decreased lipolytic activity of the enzyme. Site-directed mutagenesis revealed that hydrophobic amino acid residues centrally located in the apoC-III molecule are critical for attachment to lipid emulsion particles and consequently inhibition of LPL activity. Triglyceride-rich lipoproteins stabilize LPL and protect the enzyme from inactivating factors such as angiopoietin-like protein 4 (angptl4). The addition of either apoC-I or apoC-III to triglyceride-rich particles severely diminished their protective effect on LPL and rendered the enzyme more susceptible to inactivation by angptl4. These observations were seen using chylomicrons as well as the synthetic lipid emulsion Intralipid. In the presence of the LPL activator protein apoC-II, more of apoC-I or apoC-III was needed for displacement of LPL from the lipid/water interface. In conclusion, we show that apoC-I and apoC-III inhibit lipolysis by displacing LPL from lipid emulsion particles. We also propose a role for these apolipoproteins in the irreversible inactivation of LPL by factors such as angptl4.

Place, publisher, year, edition, pages
2013. Vol. 288, no 47, 33997-34008 p.
Keyword [en]
Apolipoproteins, Dyslipidemia, Lipolysis, Lipoprotein, Lipoprotein Metabolism, Triglyceride, Apolipoprotein C-I, Apolipoprotein C-III, Lipoprotein Lipase
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-85558DOI: 10.1074/jbc.M113.495366ISI: 000327250200041OAI: oai:DiVA.org:umu-85558DiVA: diva2:694716
Funder
Swedish Research Council, 12203Swedish Heart Lung Foundation
Available from: 2014-02-07 Created: 2014-02-06 Last updated: 2017-12-06Bibliographically 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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Larsson, MikaelVorrsjö, EvelinaOlivecrona, Gunilla

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