Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo

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.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
Lipoprotein lipase
Angiopoietin-like protein 4
Hypertriglyceridemia
Lipoprotein metabolism
Cardiovascular disease
Small molecule screening

Caraballo, RémiUmeå universitet,Kemiska institutionen(Swepub:umu)reca0008 (author)
Ericsson, MadeleneUmeå universitet,Fysiologisk kemi(Swepub:umu)maer0239 (author)
Lookene, AivarUmeå universitet,Institutionen för medicinsk biovetenskap,Tallinn University of Technology, Department of Chemistry, Tallinn, Estonia(Swepub:umu)ailo0001 (author)
Enquist, Per-AndersUmeå universitet,Kemiska institutionen(Swepub:umu)peen0006 (author)
Elofsson, MikaelUmeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)(Swepub:umu)miel0001 (author)
Nilsson, Stefan K.Umeå universitet,Institutionen för medicinsk biovetenskap (author)
Olivecrona, GunillaUmeå universitet,Fysiologisk kemi(Swepub:umu)guol0002 (author)
Umeå universitetFysiologisk kemi (creator_code:org_t)

In:Biochemical and Biophysical Research Communications - BBRC: Elsevier450:2, s. 1063-10690006-291X1090-2104

By the author/editor: Larsson, Mikael, ...; Caraballo, Rémi; Ericsson, Madele ...; Lookene, Aivar; Enquist, Per-And ...; Elofsson, Mikael; show more...; Nilsson, Stefan ...; Olivecrona, Guni ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

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