Meta-Biol

• Pathways

LPL enzyme is catalytically active as a dimer composed of two glycosylated subunits of LPL connected in a head-to-tail arrangement by non-covalent interactions. Dimeric LPL is cleaved by several proprotein convertases. FURIN and proprotein convertase subtilisin/kexin type 6 (PCSK6 aka PACE4) can cleave LPL dimer, inactivating it, resulting in subsequent increase in plasma TG concentrations (Siezen et al. 1994, Bassi et al. 2000, Jin et al. 2005). Endogenous modulators of LPL are the angiopoietin-like proteins ANGPTL3 and ANGPTL4, which can bind transiently to LPL dimer, resulting in conversion of the enzyme from a catalytically active dimer to inactive, but still folded, monomers (Liu et al. 2010, Sukonina et al. 2006). ANGPTL4 regulates plasma triglyceride concentration via the inhibition of LPL (Dijk & Kersten 2014). GWAS studies (Dewey et al. 2016, MIG and CARDIoGRAM Consortium 2016) show a strong correlation between inactivating ANGPTL4 mutants and lower levels of triglycerides and lower risk of coronary artery disease than non-carriers. Therapeutic modulation of ANGPTL4 could be a new strategy against dyslipidemia (Kersten 2016).