title: Natural Functions of PLIN2 Mediating Wnt/LiCl Signaling and Glycogen Synthase Kinase 3 (GSK3)/GSK3 Substrate-Related Effects Are Modulated by Lipid.
abstract: Belonging to the PLIN family, PLIN2 associates with lipid storage droplets (LSDs), but other functions of PLIN2 remain unclear. Here, we suggest that PLIN2 mediates Wnt signaling because PLIN2 small interfering RNA (siRNA) suppresses activation of Wnt/coreceptor pathways. The mediation in the Wnt/Frizzled pathway seems to occur from Dishevelleds to axin/glycogen synthase kinase 3(GSK3)/β-catenin complexes (AGβC) as Wnt decreases Dishevelled/PLIN2 but increases AGβC/PLIN2 associations. Augmenting cellular LSDs that affect PLIN2 associations with these proteins, oleic acid (OA) treatment inhibits Wnt-increased AGβC/PLIN2 associations and β-catenin T-cell factor signaling (β-CTS). Revealing that PLIN2 is a GSK3-associated protein, the study explored PLIN2-mediated effects on GSK3/GSK3 substrates. PLIN2 siRNA reduces inhibitory GSK3 levels and lithium chloride (LiCl)-upregulated β-catenin or CCAAT/enhancer binding protein α (c/EBPα) expression. OA treatment decreases LiCl-increased c/EBPα via PLIN2-c/EBPα dissociation. In addition to PLIN2 overexpression increasing β-CTS, PLIN2 depletion or overexpression drops or adds expression of GSK3 substrates, such as β-catenin, c/EBPα,c-Myc, cyclin D1, and insulin receptor substrate 1, and cell growth/survival. PLIN2 N or C terminus overexpression that is associated with higher levels of the substrates suggests that those substrates bind to specific regions of PLIN2. Mimicking the possible high lipid concentrations in cells in the human body under conditions of hyperlipidemia/obesity, OA-treated cells gain or reduce GSK3 substrate expression in parallel with a decrease (a Wnt-like effect) or increase in GSK3 activity, likely regulated by GSK3/PLIN2/GSK3 substrate associations.
authors.affiliation: Intramural Research Programs, National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland, USA xunxianl@mail.nih.gov Marc.Blackman@va.gov.
authors.forename: Xunxian
authors.initials: X
authors.lastname: Liu
authors.affiliation: Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Lu
authors.affiliation: ImmunoTechnology Section, Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kaimei
authors.initials: K
authors.lastname: Song
authors.affiliation: Intramural Research Programs, National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland, USA xunxianl@mail.nih.gov Marc.Blackman@va.gov.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Blackman
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D000072261:Dishevelled Proteins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018021:Lithium Chloride / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019301:Oleic Acid / Q000378:metabolism*; D000070780:Perilipin-2; D000070796:Perilipin-3; D010750:Phosphoproteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051820:TCF Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; C038196:PLIN3 protein, human; D000070780:Perilipin-2; D000070796:Perilipin-3; D010750:Phosphoproteins; C000602983:Plin2 protein, mouse; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D033921:Vesicular Transport Proteins; D019301:Oleic Acid; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride