Nimonkar, Amitabh, Weldon, Stephen, Godbout, Kevin, Panza, Darrell, Hanrahan, Susan, Cubbon, Rose, Xu, Fangmin, Trauger, John, Gao, Jiaping and Voznesensky, Andrei (2019) A lipoprotein lipase --GPI-anchored high density lipoprotein binding protein 1 fusion lowers triglycerides in mice: implications for managing familial chylomicronemia syndrome. JBC minireview series JBC., Epub a. ISSN 1083-351X

Abstract

Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex, and its derivative, the LPL-GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3(ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL-GPIHBP1 fusion protein exibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL-GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS

Item Type:	Article
Keywords:	Lipoprotein lipase, GPIHBP1, familial chylomicronemia syndrome, hyperlipidemic pancreatitis
Date Deposited:	09 Nov 2019 00:45
Last Modified:	09 Nov 2019 00:45
URI:	https://oak.novartis.com/id/eprint/37585