Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo
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
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.
Cardiac and Cardiovascular Systems
IdentifiersURN: urn:nbn:se:umu:diva-91689DOI: 10.1016/j.bbrc.2014.06.114OAI: oai:DiVA.org:umu-91689DiVA: diva2:737688
FunderSwedish Research CouncilVinnovaKnut and Alice Wallenberg FoundationCarl Tryggers foundation