title: Transgenic expression and genetic variation of Lmf1 affect LPL activity in mice and humans.
abstract: OBJECTIVE
  Lipoprotein lipase (LPL) is a principal enzyme in lipoprotein metabolism, tissue lipid utilization, and energy metabolism. LPL is synthesized by parenchymal cells in adipose, heart, and muscle tissues followed by secretion to extracellular sites, where lipolyic function is exerted. The catalytic activity of LPL is attained during posttranslational maturation, which involves glycosylation, folding, and subunit assembly within the endoplasmic reticulum. A lipase-chaperone, lipase maturation factor 1 (Lmf1), has recently emerged as a critical factor in this process. Previous studies demonstrated that loss-of-function mutations of Lmf1 result in diminished lipase activity and severe hypertriglyceridemia in mice and human subjects. The objective of this study is to investigate whether, beyond its role as a required factor in lipase maturation, variation in Lmf1 expression is sufficient to modulate LPL activity in vivo.
  
  
  RESULTS
  To assess the effects of Lmf1 overexpression in adipose and muscle tissues, we generated aP2-Lmf1 and Mck-Lmf1 transgenic mice. Characterization of relevant tissues revealed increased LPL activity in both mouse strains. In the omental and subcutaneous adipose depots, Lmf1 overexpression was associated with increased LPL specific activity without changes in LPL mass. In contrast, increased LPL activity was due to elevated LPL protein level in heart and gonadal adipose tissue. To extend these studies to humans, we detected association between LMF1 gene variants and postheparin LPL activity in a dyslipidemic cohort.
  
  
  CONCLUSIONS
  Our results suggest that variation in Lmf1 expression is a posttranslational determinant of LPL activity.
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Hosseini
authors.forename: Nicole
authors.initials: N
authors.lastname: Ehrhardt
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Ching-Mei
authors.initials: CM
authors.lastname: Lai
authors.forename: Hui Z
authors.initials: HZ
authors.lastname: Mao
authors.forename: Jo-Ling
authors.initials: JL
authors.lastname: Liao
authors.forename: Elina
authors.initials: E
authors.lastname: Nikkola
authors.forename: André
authors.initials: A
authors.lastname: Bensadoun
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Mark H
authors.initials: MH
authors.lastname: Doolittle
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.forename: Miklós
authors.initials: M
authors.lastname: Péterfy
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004247:DNA / Q000235:genetics*; D004734:Energy Metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism
chemical_list: C546367:LMF1 protein, mouse; D008565:Membrane Proteins; D004247:DNA; D008071:Lipoprotein Lipase