Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

Kremer, Andreas E.; Martens, Job J.W.W.; Kulik, Wim; Ruëff, Franziska; Kuiper, Edith M. M.; Buuren, Henk R. van; Erpecum, Karel J. van; Kondrackienė, Jūratė; Prieto, Jesús; Rust, Christian; Geenes, Victoria; Williamson, Catherine; Moolenaar, Wouter H.; Beuers, Ulrich; Elferink, Ronald P.J. Oude

doi:10.1053/j.gastro.2010.05.009

Cited by 341 publications

(346 citation statements)

References 47 publications

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“…29,30 However, the initiation of therapy with obeticholic acid at a dose of 5 mg, with adjustment up to 10 mg if appropriate, was associated with a lower rate of discontinuation owing to pruritus (one patient) than was starting at 10 mg (seven patients). The mechanism for obeticholic acid-related pruritus is unclear; although autotaxin has been shown to correlate with cholestatic pruritus, 25 there was no correlation in this trial. There were no other changes in quality of life, as assessed by the PBC-40 questionnaire, among patients who were treated with obeticholic acid.…”

Section: Discussionmentioning

confidence: 54%

“…Autotaxin is the only variable that has so far been identified to correlate with the severity of cholestatic pruritus. 25 However, post hoc analysis showed no correlation between autotaxin activity and patient-reported measures of pruritus severity (according to the visual-analogue scale, 5-D questionnaire, or PBC-40 itch scores) (Fig. S9 in the Supplementary Appendix).…”

Section: Safety and Side Effectsmentioning

confidence: 97%

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A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

et al. 2016

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Section: Discussionmentioning

confidence: 54%

Section: Safety and Side Effectsmentioning

confidence: 97%

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

et al. 2016

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“…LPA acts as a ligand for several LPA receptors (LPARs) showing overlapping activities. The ATX-LPA signalling axis is vital for embryonic development and has been implicated in many (patho)physiological processes, which include vascular development 5 , cancer metastasis 6 , and other human diseases, such as fibrosis 7 and cholestatic pruritus 8 .…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid produced by Autotaxin acts as an allosteric modulator of its catalytic efficiency

Salgado-Polo

Fish

Matsoukas

et al. 2018

Preprint

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Autotaxin is a secreted phosphodiesterase that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key cellular responses such as migration, proliferation and survival, implicating ATX-LPA signalling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, the "pocket" and the "tunnel". Here, we revisit the kinetics of the ATX catalytic cycle in light of allosteric regulation, dissecting the different steps and pathways that lead to LPC hydrolysis. Consolidating all experimental kinetics data to a comprehensive catalytic model supported by molecular modelling simulations, suggests a positive feedback mechanism, regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend current understanding of ATX hydrolysis in light of the allosteric regulation by produced LPA species, and have implications for the design and application of orthosteric and allosteric ATX inhibitors.

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“…Genetic reasons (e.g., modifiers reflecting underlying cholestatic predisposition [108]) or differences in immune reaction profiles between the patients [109] may be involved in causing the pruritic predisposition. At some level, the mechanisms causing cholestatic pruritus seem to involve the conversion of lysophosphatidylcholine into lysophosphatidic acid (LPA) by autotaxin [110]. Autotaxin activity in cholestatic patients correlates with pruritus, which is not the case for other candidate pruritogens like bile salts, histamine, tryptase, substance P or endogenous opioids.…”

Section: Cholestatic Pruritusmentioning

confidence: 99%

Update on primary sclerosing cholangitis

Karlsen

Schrumpf

Boberg

2010

Digestive and Liver Disease

104

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SummaryPrimary sclerosing cholangitis (PSC) remains one of the most challenging conditions of clinical hepatology. There has been a steady growth in research to overcome this fact and the present review aims at summarizing the most recently published literature. The main emphasis will be put on the link of recent pathogenetic insights to clinical characteristics and patient management. With regard to pathogenesis, there is no consensus yet as to whether immune mediated injury or factors related to bile acid physiology are the most important. It also remains to be clarified whether PSC is a mixed bag of various secondary etiologies yet to be defined, or a disease entity predominantly represented by sclerosing cholangitis in the context of inflammatory bowel disease. Most important, there is no available medical therapy with proven influence on clinical end points, and timing of liver transplantation and patient follow-up are challenging due to the unpredictable and high risk of cholangiocarcinoma. Ó

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Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

Cited by 341 publications

References 47 publications

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

Lysophosphatidic acid produced by Autotaxin acts as an allosteric modulator of its catalytic efficiency

Update on primary sclerosing cholangitis

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