Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation

https://doi.org/10.1016/j.bbadis.2021.166239Get rights and content
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Highlights

  • ATX activity is inhibited by bile salts and bile salt-like compounds like pregnanedioldisulfate.

  • ATX mRNA levels in cells are feedback regulated by its product LPA through activation of LPA receptors

  • In a cholestatic mouse model increased plasma bile salt levels correlate with increased ATX levels

  • High serum levels of bile salt(-like) compounds in cholestasis inhibit ATX activity leading to upregulation of ATX expression

Abstract

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.

Abbreviations

ATX
autotaxin
CDC
chenodeoxycholate
GC
glycocholate
GCDC
glycochenodeoxycholate
GLC-3S
glycolithocholate-3-sulfate
GUDC
glycoursodeoxycholate
HPLC
high pressure liquid chromatography
ICP
intrahepatic cholestasis of pregnancy
LPA
lysophosphatidic acid
LPC
lysophosphatidylcholine
PBC
primary biliary cholangitis
PM
progesterone metabolite
PM-2DiS
5α-pregnan-3α,-20α-diol-3,20-disulfate
PM-3S
5β-pregnan-3α,-20α-diol-3-sulfate
TC
taurocholate
TCDC
taurochenodeoxycholate
TLC
taurolithocholate
TLC-3S
taurolithocholate-3-sulfate
TUDC
tauroursodeoxycholate
UDC
ursodeoxycholate

Keywords

Lysophosphatidic acid
Lysophosphatidylcholine
Bile salts
Progesterone metabolites
Steroids.

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