Obeticholic Acid Protects against Lipopolysaccharide-Induced Fetal Death and Intrauterine Growth Restriction through Its Anti-Inflammatory Activity.
Farnesoid X receptor (FXR) is expressed in human and rodent placentas. Nevertheless, its function remains obscure. This study investigated the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, on LPS-induced fetal death and intrauterine growth restriction. All pregnant mice except controls were i.p. injected with LPS (100 μg/kg) daily from gestational day (GD) 15 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD13 to GD17. As expected, placental FXR signaling was activated by OCA. OCA pretreatment protected against LPS-induced fetal death. In addition, OCA pretreatment alleviated LPS-induced reduction of fetal weight and crown-rump length. Additional experiments showed that OCA inhibited LPS-evoked TNF-α in maternal serum and amniotic fluid. Moreover, OCA significantly attenuated LPS-induced upregulation of placental proinflammatory genes including Tnf-α, Il-1β, IL-6, Il-12, Mip-2, Kc, and Mcp-1 By contrast, OCA elevated anti-inflammatory cytokine IL-10 in maternal serum, amniotic fluid, and placenta. Further analysis showed that OCA blocked nuclear translocation of NF-κB p65 and p50 subunits in trophoblast giant cells of the labyrinth zone. These results provide a mechanistic explanation for placental FXR-mediated anti-inflammatory activity. Overall, this study provides evidence for roles of FXR as an important regulator of placental inflammation.
Department of Toxicology, Anhui Medical University, Hefei 230032, China.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.|Department of Histology and Embryology, Anhui Medical University, Hefei 230032, China.
Yuan-Hua
YH
Chen
Department of Toxicology, Anhui Medical University, Hefei 230032, China.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.
Xiao-Guang
XG
Hu
Department of Toxicology, Anhui Medical University, Hefei 230032, China.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.
Yan
Y
Zhou
Department of Toxicology, Anhui Medical University, Hefei 230032, China.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.
Zhen
Z
Yu
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Lin
L
Fu
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Gui-Bin
GB
Zhang
Department of Toxicology, Anhui Medical University, Hefei 230032, China.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.
Qing-Li
QL
Bo
Department of Toxicology, Anhui Medical University, Hefei 230032, China.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.
Hua
H
Wang
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Cheng
C
Zhang
Department of Toxicology, Anhui Medical University, Hefei 230032, China; xudex@126.com.|Laboratory of Environmental Toxicology, Hefei 230032, China; and.
De-Xiang
DX
Xu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications* / Q000276:immunology; D005260:Female; D005313:Fetal Death / Q000209:etiology / Q000517:prevention & control*; D005317:Fetal Growth Retardation / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000276:immunology; D011247:Pregnancy; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
D000893:Anti-Inflammatory Agents; D002635:Chenodeoxycholic Acid; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid