title: Soluble CLEC2 Extracellular Domain Improves Glucose and Lipid Homeostasis by Regulating Liver Kupffer Cell Polarization.
abstract: The polarization of tissue resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to positively impact obesity and insulin resistance. Here we show that the soluble form of the extracellular domain (ECD) of C-type lectin-like receptor 2, CLEC2, regulates Kupffer cell polarization in the liver and improves glucose and lipid parameters in diabetic animal models. Over-expression of Fc-CLEC2(ECD) in mice via in vivo gene delivery, or injection of recombinant Fc-CLEC2(ECD) protein, results in a reduction of blood glucose and liver triglyceride levels and improves glucose tolerance. Furthermore, Fc-CLEC2(ECD) treatment improves cytokine profiles and increases both the M2 macrophage population and the genes involved in the oxidation of lipid metabolism in the liver. These data reveal a previously unidentified role for CLEC2 as a regulator of macrophage polarity, and establish CLEC2 as a promising therapeutic target for treatment of diabetes and liver disease.
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Xinle
authors.initials: X
authors.lastname: Wu
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lemon
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Coberly
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Rulifson
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Jonitha
authors.initials: J
authors.lastname: Gardner
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D016764:Cell Polarity; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D012995:Solubility
chemical_list: C529518:CLEC-2 protein, mouse; D037181:Lectins, C-Type; D011961:Receptors, Fc; D011994:Recombinant Proteins; D005947:Glucose
keywords: CLEC2; Diabetes; Dyslipidemia; Inflammation; Kupffer cell; Macrophage