Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo
| Autor: | Mikael Elofsson, Per-Anders Enquist, Madelene Ericsson, Stefan K. Nilsson, Rémi Caraballo, Gunilla Olivecrona, Aivar Lookene, Mikael Larsson |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Very low-density lipoprotein Low-density lipoprotein receptor-related protein 8 Apolipoprotein B Pyridines Biophysics Heterocyclic Compounds 4 or More Rings Biochemistry Small Molecule Libraries Structure-Activity Relationship Internal medicine Enzyme Stability medicine Angiopoietin-Like Protein 4 Animals Molecular Biology Triglycerides Hypolipidemic Agents Hypertriglyceridemia Mice Knockout Lipoprotein lipase biology Chemistry nutritional and metabolic diseases Lipid metabolism Cell Biology Postprandial Period medicine.disease Mice Inbred C57BL Lipoprotein Lipase Apolipoproteins Endocrinology Postprandial Apolipoprotein A-V biology.protein lipids (amino acids peptides and proteins) Protein Multimerization Angiopoietins Dyslipidemia Protein Binding |
| Zdroj: | Biochemical and Biophysical Research Communications. 450:1063-1069 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2014.06.114 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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