Journal
FASEB JOURNAL
Volume 27, Issue 8, Pages 3090-3099Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-228759
Keywords
lipid droplets; lipid accumulation; lipid metabolism; HEK293 cells; macrophages
Categories
Funding
- Swedish Research Council [12659]
- Swedish Heart-Lung Foundation
- Swedish Diabetes Foundation
- Swedish Foundation for Strategic Research
- Karolinska Institutet Funds
- Research Corporation for Science Advancement
- Novo Nordisk Fonden [NNF13OC0004973] Funding Source: researchfish
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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 -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.
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