title: Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo.
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.
authors.affiliation: Umeå University, Medical Biosciences, Umeå, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Umeå University, Department of Chemistry, Umeå, Sweden.
authors.forename: Rémi
authors.initials: R
authors.lastname: Caraballo
authors.affiliation: Umeå University, Medical Biosciences, Umeå, Sweden.
authors.forename: Madelene
authors.initials: M
authors.lastname: Ericsson
authors.affiliation: Tallinn University of Technology, Department of Chemistry, Tallinn, Estonia; Umeå University, Medical Biosciences, Umeå, Sweden.
authors.forename: Aivar
authors.initials: A
authors.lastname: Lookene
authors.affiliation: Umeå University, Department of Chemistry, Umeå, Sweden.
authors.forename: Per-Anders
authors.initials: PA
authors.lastname: Enquist
authors.affiliation: Umeå University, Department of Chemistry, Umeå, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.affiliation: Umeå University, Medical Biosciences, Umeå, Sweden.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Nilsson
authors.affiliation: Umeå University, Medical Biosciences, Umeå, Sweden. Electronic address: gunilla.olivecrona@medbio.umu.se.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000235:genetics; D004795:Enzyme Stability; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019518:Postprandial Period; D011485:Protein Binding; D055503:Protein Multimerization; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood*
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D006576:Heterocyclic Compounds, 4 or More Rings; D000960:Hypolipidemic Agents; D011725:Pyridines; D054852:Small Molecule Libraries; D014280:Triglycerides; C000591751:compound 50F10; D008071:Lipoprotein Lipase
keywords: Angiopoietin-like protein 4; Cardiovascular disease; Hypertriglyceridemia; Lipoprotein lipase; Lipoprotein metabolism; Small molecule screening