Pro-fibrotic activity of lysophosphatidic acid in adipose tissue: In vivo and in vitro evidence

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• 作者：Chlo茅 Rancoule ; Manon Viaud ; S ; ra Gres ; Nathalie Viguerie ; Pauline Decaunes ; Anne Bouloumi茅 ; Dominique Langin ; Jean-Loup Basc ; s ; Philippe Valet ; Jean S茅bastien Saulnier-Blache
• 关键词：Lysophosphatidic acid ; Adipose tissue ; Fibrosis
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：January, 2014
• 年：2014
• 卷：1841
• 期：1
• 页码：88-96
• 全文大小：487 K

文摘

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), TGF尾, CTGF and 伪SMA] 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 (5 mg/kg/day ip for 7 weeks); and (ii) in vitro in human AT explants in primary culture for 72 h in the presence of oleoyl-LPA (10 渭M) and/or Ki16425 (10 渭M) and/or the HIF-1伪 inhibitor YC-1 (100 渭M). 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, TGF尾 and 伪SMA 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-1伪.