title: The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans.
abstract: Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)-associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program. Structure modeling using 3D-JigSaw and the Chimera package revealed that the Pro251 allele disrupts a predicted α-helix in PLIN2. Analyses of macrophages from individuals carrying Ser251Pro variants and human embryonic kidney 293 (HEK293) cells stably transfected with either of the alleles demonstrated that the Pro251 variant causes increased lipid accumulation and decreased lipolysis. Analysis of LD size distribution in stably transfected cells showed that the minor Pro251 allele resulted in an increased number of small LDs per cell and increased perilipin 3 protein expression levels as compared with cells carrying the major Ser251 allele. Genotyping of 2113 individuals indicated that the Pro251 variant is associated with decreased plasma triglyceride and very low-density lipoprotein concentrations. Altogether, these data provide the first evidence of a polymorphism in PLIN2 that affects PLIN2 function and may influence the development of metabolic and cardiovascular diseases.
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Magné
authors.forename: Anna
authors.initials: A
authors.lastname: Aminoff
authors.forename: Jeanna
authors.initials: J
authors.lastname: Perman Sundelin
authors.forename: Maria Nastase
authors.initials: MN
authors.lastname: Mannila
authors.forename: Peter
authors.initials: P
authors.lastname: Gustafsson
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Annika
authors.initials: A
authors.lastname: Wernerson
authors.forename: Greta
authors.initials: G
authors.lastname: Bauer
authors.forename: Laura
authors.initials: L
authors.lastname: Listenberger
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Neville
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Ewa
authors.initials: E
authors.lastname: Ehrenborg
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008055:Lipids / Q000032:analysis; D008066:Lipolysis / Q000235:genetics*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000070780:Perilipin-2; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
chemical_list: D008055:Lipids; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D014280:Triglycerides
keywords: HEK293 cells; lipid accumulation; lipid droplets; lipid metabolism; macrophages