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 deficiency") 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 copurifies 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.
Highlights
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
These results suggest that the combined lipase deficiency phenotype associated with the cld mutation extends to a third member of the triglyceride lipase family, namely endothelial lipase (EL)
We report in this study that in addition to LPL and HL, EL requires Lmf1 to attain enzymatic activity
Summary
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. 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]. Modulation of EL activity in mice leads to changes in plasma HDL levels similar to those of HL [18,19,20], reflecting their related substrate specificities. Consistent with their multifaceted involvement in lipoprotein metabolism, LPL, HL, and EL are strongly associated with plasma lipid levels in the general population [21].
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