title: Lipase maturation factor 1 is required for endothelial lipase activity.
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.
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
authors: Osnat
authors: O
authors: Ben-Zeev
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Maryam
authors: M
authors: Hosseini
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
authors: Ching-Mei
authors: CM
authors: Lai
authors: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Nicole
authors: N
authors: Ehrhardt
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
authors: Howard
authors: H
authors: Wong
authors: Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.
authors: Angelo B
authors: AB
authors: Cefalù
authors: Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.
authors: Davide
authors: D
authors: Noto
authors: Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.
authors: Maurizio R
authors: MR
authors: Averna
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
authors: Mark H
authors: MH
authors: Doolittle
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: David_McLaren@merck.com.
authors: Miklós
authors: M
authors: Péterfy
mesh_terms: D000818:Animals; D002846:Chromatography, Affinity; D018274:Electroporation; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010957:Plasmids; D014162:Transfection
chemical_list: C504173:LIPC protein, human; C546366:LMF1 protein, human; D008565:Membrane Proteins; C410382:LIPG protein, human; D008049:Lipase; D008071:Lipoprotein Lipase