The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice

Int Immunopharmacol. 2020 Jun:83:106442. doi: 10.1016/j.intimp.2020.106442. Epub 2020 Apr 2.

Abstract

The disorder of bile acid metabolism is a common feature during pregnancy, which leads to adverse birth outcomes and maternal damage effects. However, the cause and therapy about the disorder of bile acid metabolism are still poor. Microbial infection often occurs in pregnant women, which can induce the disorder of bile acid metabolism in adult mice. Here, this study observed the acute effect of lipopolysaccharide (LPS) on maternal bile acid of pregnant mice at gestational day 17 and the protective effect of obeticholic acid (OCA) pretreatment, a potent agonist of bile acid receptor farnesoid X receptor (FXR). The results showed LPS significantly increased the level of maternal serum and disordered bile acids components of maternal serum and liver, which were ameliorated by OCA pretreatment with obviously reducing the contents of CA, TCA, DCA, TCDCA, CDCA, GCA and TDCA in maternal serum and DCA, TCA, TDCA, TUDCA, CDCA and TCDCA in maternal liver. Furthermore, we investigated the effects of OCA on LPS-disrupted bile acid metabolism in maternal liver. LPS disrupted maternal bile acid profile by decreasing transport and metabolism with hepatic tight junctions of bile acid in pregnant mice. OCA obviously increased the protein level of nuclear FXR and regulated its target genes involving in the metabolism of bile acid, which was characterized by the lower expression of bile acid synthase CYP7A1, the higher expression of CYP3A and the higher mRNA level of transporter Mdr1a/b. This study provided the evidences that LPS disrupted bile acid metabolism in the late stage of pregnant mice and OCA pretreatment played the protective role on it by activating FXR.

Keywords: Bile acid disorder; Farnesoid X receptor; Lipopolysaccharide; Obeticholic acid; Pregnancy.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Bile Acids and Salts / metabolism*
  • Cells, Cultured
  • Chenodeoxycholic Acid / analogs & derivatives*
  • Chenodeoxycholic Acid / metabolism
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Female
  • Gene Expression Regulation
  • Humans
  • Lipopolysaccharides / metabolism
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Mice, Inbred ICR
  • Pregnancy
  • RNA-Binding Proteins / agonists
  • Tight Junctions / pathology

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Bile Acids and Salts
  • Fxr1h protein, mouse
  • Lipopolysaccharides
  • RNA-Binding Proteins
  • obeticholic acid
  • Chenodeoxycholic Acid
  • multidrug resistance protein 3
  • CYP7A1 protein, human
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse