TY - JOUR
T1 - Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation
AU - Langedijk, Jacqueline A. G. M.
AU - Tolenaars, Dagmar
AU - Bolier, Ruth
AU - Lee, Yi-T.
AU - Meurs, Amber
AU - Williamson, Catherine
AU - Adorini, Luciano
AU - van de Graaf, Stan F. J.
AU - Beuers, Ulrich
AU - Elferink, Ronald Oude
N1 - Funding Information: This research was funded by a TOP ZonMW grant (# 40-00812-98-10054 ) and a grant from the Dioraphte Foundation (# 1115 ) to R.O.E. Publisher Copyright: © 2021 Amsterdam UMC, Amsterdam, The Netherlands
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Background: Autotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. Methods: Bile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. Results: Surprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. Conclusions: Multiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.
AB - Background: Autotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. Methods: Bile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. Results: Surprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. Conclusions: Multiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.
KW - Bile salts
KW - Lysophosphatidic acid
KW - Lysophosphatidylcholine
KW - Progesterone metabolites
KW - Steroids.
UR - http://www.scopus.com/inward/record.url?scp=85112256769&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbadis.2021.166239
DO - https://doi.org/10.1016/j.bbadis.2021.166239
M3 - Article
C2 - 34389475
SN - 0925-4439
VL - 1867
JO - Biochimica et Biophysica Acta-Molecular Basis of Disease
JF - Biochimica et Biophysica Acta-Molecular Basis of Disease
IS - 11
M1 - 166239
ER -