Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

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Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2021-08-10 , DOI: 10.1016/j.bbadis.2021.166239
Jacqueline A G M Langedijk ₁ , Dagmar Tolenaars ₁ , Ruth Bolier ₁ , Yi-Té Lee ₁ , Amber Meurs ₁ , Catherine Williamson ₂ , Luciano Adorini ₃ , Stan F J van de Graaf ₁ , Ulrich Beuers ₁ , Ronald Oude Elferink ₁

Affiliation

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.

中文翻译：

胆盐和胆盐样分子对自分泌运动因子的抑制通过反馈调节增加其表达

背景

Autotaxin 是一种酶，可将溶血磷脂转化为溶血磷脂酸 (LPA)，这是一种通过一系列 LPA 受体的高效信号分子。因此，重要的是研究哪些因素在调节 ATX 表达中起作用。由于我们已经报道了各种形式的胆汁淤积患者的 ATX 水平显着增加，因此我们开始了一项研究，以揭示影响 ATX 酶活性及其体外和体内表达水平的因素。

方法

来自胆汁淤积患者的胆汁通过 HPLC 分离并分析 ATX 活性的调节。在刺激或抑制 LPA 信号传导后，在成纤维细胞中测量 ATX 表达。

结果

令人惊讶的是，ATX 的活性受到其大多数形式的产物 LPA 的刺激，但它受到胆汁盐和胆汁盐样分子的抑制，特别是被 3-OH 硫酸化胆汁盐和硫酸化黄体酮代谢物抑制，这些代谢物已知在慢性胆汁淤积和胆汁淤积过程中积累怀孕，分别。LPA 对成纤维细胞的激活使 ATX 表达降低了 72%。相反，LPA 信号的抑制使 ATX 表达增加了 3 倍，表明 LPA 信号的强反馈调节。在成纤维细胞中，我们可以验证胆汁盐对 ATX 活性的抑制会诱导其表达。此外，小鼠胆汁淤积的诱导导致血浆 ATX 活性增加。