Lithocholic acid activates mTOR signaling inducing endoplasmic reticulum stress in placenta during intrahepatic cholestasis of pregnancy

Aims: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which increases risks of adverse fetal outcomes. However, the pathophysiology is not fully understood. Here, we explored the roles of mTOR signaling and ER stress in placenta during ICP. Materials and methods: Placental tissues were collected from normal and ICP pregnancies. mTOR signaling and endoplasmic reticulum stress were detected by immunohistochemistry in the placenta. The human placenta trophoblast cell line HTR-8/SVneo was used in vitro experiment. Key findings: ICP placenta displayed histological abnormalities with fewer trophoblasts. Moreover, the expression of Bip and the phosphorylation of pS6(S235/236) or pAkt(S473) were higher comparing with normal placenta. In in vitro studies, the bile acids specifically to lithocholic acid rather than taurocholic acid or ursodeoxycholic acid, drastically increased the phosphorylation of pS6K1(T389), pS6(S235/236), or pAkt(S473), whereas the mTOR inhibitor can prohibit the upregulation. Similarly, the expressions of IRE1 alpha and BiP increased sharply under lithocholic acid (20 mu M) administration, while the same inhibitor can also decrease the expression. Additionally, transmission electron microscopy showed enlarged endoplasmic reticulum lumen under the lithocholic acid treatment. Furthermore, the cell viability reduced sharply under treatment with different dose of lithocholic acid. The mTOR inhibitor can reverse the decrease of cell viability to some extent. Significance: Bile acid can activate mTOR signaling which resulted in endoplasmic reticulum stress, leading to trophocyte viability decrease. mTOR pathway activation may be associated with the pathophysiology of ICP.