Lipase maturation factor 1 is required for endothelial lipase activity

Abstract

This article is available online at http://www.jlr.org hydrolyze two principal lipid substrates associated with lipoprotein particles, triglycerides (TGs), and phospholipids. The released fatty acids (FAs) resulting from lipase hydrolysis are taken up by subjacent tissue and used for energy storage (adipose), oxidation, and energy production (skeletal muscle and heart) and the synthesis of bioactive metabolites (variety of tissues).LPL is principally a TG lipase involved in the metabolism of TG-rich lipoproteins (chylomicrons and very-lowdensity lipoproteins) in adipose and muscle and heart tissues ( 1 ). Its defi ciency and overexpression have been linked to metabolic abnormalities such as hypertriglyceridemia, insulin resistance, and cardiomyopathy, indicating the critical role of this enzyme in TG metabolism ( 4-10 ). Unlike LPL, HL has comparable TG lipase and phospholipase activities and is involved in the hepatic metabolism of high-density lipoprotein (HDL) as well as apolipoprotein B (apoB)-containing lipoproteins (LpBs) ( 11,12 ). Overexpression of HL reduces plasma levels of HDL and LpBs, whereas HL defi ciency has the opposite effect ( 13-16 ). EL is predominantly a phospholipase affecting HDL metabolism, but it also shares a redundant role with HL in the metabolism of LpBs ( 11,17 ). Indeed, modulation of EL activity in mice leads to changes in plasma HDL levels similar to those of HL (18)(19)(20), refl ecting their related substrate specifi cities. Consistent with their multifaceted involvement in lipoprotein metabolism, LPL, HL, and EL are strongly associated with plasma lipid levels in the general population ( 21 ). Abstract Lipase maturation factor 1 (Lmf1) is an endoplasmic reticulum (ER) membrane protein involved in the posttranslational folding and/or assembly of lipoprotein lipase (LPL) and hepatic lipase (HL) into active enzymes.Mutations in Lmf1 are associated with diminished LPL and HL activities ("combined lipase defi ciency") and result in severe hypertriglyceridemia in mice as well as in human subjects. Here, we investigate whether endothelial lipase (EL) also requires Lmf1 to attain enzymatic activity. We demonstrate that cells harboring a ( cld ) loss-of-function mutation in the Lmf1 gene are unable to generate active EL, but they regain this capacity after reconstitution with the Lmf1 wild type. Furthermore, we show that cellular EL copurifi es with Lmf1, indicating their physical interaction in the ER. Finally , we determined that post-heparin phospholipase activity in a patient with the LMF1 W464X mutation is reduced by more than 95% compared with that in controls. Thus, our study indicates that EL is critically dependent on Lmf1 for its maturation in the ER and demonstrates that Lmf1 is a required factor for all three vascular lipases, LPL, HL, and EL. The vascular lipase family is composed of three evolutionarily related enzymes, lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL) ( 1-3 ). Localized to the luminal face of tissue capillaries, lipases

Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism

“…Lipase maturation factor 1 (LMF1) dimerizes and activates LPL, as well as other related lipases, namely hepatic lipase 16 and endothelial lipase 17 . A specific chaperone called Sel1L stabilizes the LPL-LMF1 complex 18 .…”

Biochemistry and pathophysiology of intravascular and intracellular lipolysis

“…Two other enzymes of the same family, HL and EL, participate in the remodeling of plasma lipoproteins. Like LPL, HL and EL are secreted as homodimers Griffon et al 2009), require LMF1 for secretion, and bind avidly to heparin (Peterfy et al 2007;Ben-Zeev et al 2010). In vivo, both are presumed to bind HSPGs and can be released from their binding sites with a bolus of heparin (Krauss et al 1973;Fuki et al 2003;Badellino et al 2006).…”

Lipoprotein lipase: From gene to atherosclerosis

“…LMF1 is an ER membrane protein involved in the posttranslational folding, assembly and stabilization of active LPL homodimer [17]. Without LMF1 in the ER, LPL homodimers are rapidly dissociated to misfolded monomers which are prone to aggregation [18]. There is an intracellular pool of inactive LPL containing aggregated misfolded LPL, which is destined for ER degradation [19,20].…”