title: Pro-fibrotic activity of lysophosphatidic acid in adipose tissue: in vivo and in vitro evidence.
abstract: Lysophosphatidic acid (LPA) is a pro-fibrotic mediator acting via specific receptors (LPARs) and is synthesized by autotaxin, that increases with obesity. We tested whether LPA could play a role in adipose tissue (AT)-fibrosis associated with obesity. Fibrosis [type I, III, and IV collagens (COL), fibronectin (FN), TGFβ, CTGF and αSMA] and inflammation (MCP1 and F4/80) markers were quantified: (i) in vivo in inguinal (IAT) and perigonadic (PGAT) AT from obese-diabetic db/db mice treated with the LPAR antagonist Ki16425 (5mg/kg/day ip for 7 weeks); and (ii) in vitro in human AT explants in primary culture for 72h in the presence of oleoyl-LPA (10μM) and/or Ki16425 (10μM) and/or the HIF-1α inhibitor YC-1 (100μM). Treatment of db/db mice with Ki16425 reduced Col I and IV mRNAs in IAT and PGAT while Col III mRNAs were only reduced in IAT. This was associated with reduction of COL protein staining in both IAT and PGAT. AT explants showed a spontaneous and time-dependent increase in ATX expression and production of LPA in the culture medium, along with increased levels of Col I and III, TGFβ and αSMA mRNAs and of COL protein staining. In vitro fibrosis was blocked by Ki16425 and was further amplified by oleoyl-LPA. LPA-dependent in vitro fibrosis was blocked by co-treatment with YC1. Our results show that endogenous and exogenous LPA exert a pro-fibrotic activity in AT in vivo and in vitro. This activity could be mediated by an LPA1R-dependent pathway and could involve HIF-1α.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1048, Toulouse Cedex 4, France; Université de Toulouse, Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, BP84225, 31432 Toulouse Cedex 4, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Rancoule
authors.forename: Manon
authors.initials: M
authors.lastname: Viaud
authors.forename: Sandra
authors.initials: S
authors.lastname: Gres
authors.forename: Nathalie
authors.initials: N
authors.lastname: Viguerie
authors.forename: Pauline
authors.initials: P
authors.lastname: Decaunes
authors.forename: Anne
authors.initials: A
authors.lastname: Bouloumié
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D005355:Fibrosis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000633:toxicity*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D011422:Propionates / Q000633:toxicity*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; C541116:ACTA2 protein, human; C558396:Acta2 protein, mouse; D000199:Actins; D020536:Enzyme Activators; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D016212:Transforming Growth Factor beta; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D003094:Collagen; C032881:lysophosphatidic acid
keywords: Adipose tissue; Fibrosis; Lysophosphatidic acid