Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo |
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Authors: | Mikael Larsson Rémi Caraballo Madelene Ericsson Aivar Lookene Per-Anders Enquist Mikael Elofsson Stefan K Nilsson Gunilla Olivecrona |
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Institution: | 1. Umeå University, Medical Biosciences, Umeå, Sweden;2. Umeå University, Department of Chemistry, Umeå, Sweden;3. Tallinn University of Technology, Department of Chemistry, Tallinn, Estonia |
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Abstract: | Patients at increased cardiovascular risk commonly display high levels of plasma triglycerides (TGs), 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. On injection to hypertriglyceridemic apolipoprotein A-V deficient mice the compound ameliorated the postprandial response after an olive oil gavage. This is a potential lead compound for the development of drugs that could reduce the residual risk associated with elevated plasma TGs in dyslipidemia. |
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Keywords: | ANGPTL4 angiopoietin-like protein 4 apo apolipoprotein BSA bovine serum albumin BW body weight CVD cardiovascular disease FA fatty acid HDL high-density lipoprotein i p intraperitoneal i v intravenous LDL low-density lipoprotein LPL lipoprotein lipase SPR surface plasmon resonance S/B signal-to-background ratio S/N signal-to-noise ratio TG triglyceride TRLs triglyceride-rich lipoproteins VLDL very low-density lipoprotein Z&prime Z-factor %CV coefficient of variance |
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