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Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study

There is accumulating evidence that the circulatory levels of autotaxin (ATX) and lysophosphatidic acid (LPA) are increased in patients with severe liver disease. However, the potential role of the ATX-LPA axis in hepatic encephalopathy (HE) remains unclear. Our study aimed to investigate the role o...

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Autores principales: Sepehrinezhad, Ali, Shahbazi, Ali, Joghataei, Mohammad Taghi, Larsen, Fin Stolze, Sahab Negah, Sajad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394058/
https://www.ncbi.nlm.nih.gov/pubmed/37528089
http://dx.doi.org/10.1038/s41419-023-06022-5
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author Sepehrinezhad, Ali
Shahbazi, Ali
Joghataei, Mohammad Taghi
Larsen, Fin Stolze
Sahab Negah, Sajad
author_facet Sepehrinezhad, Ali
Shahbazi, Ali
Joghataei, Mohammad Taghi
Larsen, Fin Stolze
Sahab Negah, Sajad
author_sort Sepehrinezhad, Ali
collection PubMed
description There is accumulating evidence that the circulatory levels of autotaxin (ATX) and lysophosphatidic acid (LPA) are increased in patients with severe liver disease. However, the potential role of the ATX-LPA axis in hepatic encephalopathy (HE) remains unclear. Our study aimed to investigate the role of the ATX-LPA signaling pathway in mice with thioacetamide (TAA) induced acute HE. To show the role of the ATX-LPA axis in the context of HE, we first measured the involvement of ATX-LPA in the pathogenesis of TAA-induced acute HE. Then, we compared the potential effects of ATX inhibitor (HA130) on astrocyte responses at in vitro and gut–liver–brain axis at in vivo levels. The inflammatory chemokine (C–C motif) ligand 3 was significantly increased in the hyperammonemic condition and could be prevented by ATX inhibition in astrocytes at in vitro level. Further statistical tests revealed that plasma and tissue pro-inflammatory cytokines were inhibited by HA130 in mice. Furthermore, the stage of HE was significantly improved by HA130. The most surprising result was that HA130 alleviated immune infiltrating cells in the liver and intestine and decreased mucus-secreting cells in the intestine. Further analysis showed that the levels of liver enzymes in serum were significantly decreased in response to ATX inhibition. Surprisingly, our data indicated that HA130 could recover permeabilization of the blood-brain barrier, neuroinflammation, and recognition memory. Besides that, we found that the changes of Interleukin-1 (IL-1) and aquaporin-4 (AQP4) in HE might have a connection with the glymphatic system based on bioinformatics analyses. Taken together, our data showed that the ATX-LPA axis contributes to the pathogenesis of HE and that inhibition of ATX improves HE.
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spelling pubmed-103940582023-08-03 Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study Sepehrinezhad, Ali Shahbazi, Ali Joghataei, Mohammad Taghi Larsen, Fin Stolze Sahab Negah, Sajad Cell Death Dis Article There is accumulating evidence that the circulatory levels of autotaxin (ATX) and lysophosphatidic acid (LPA) are increased in patients with severe liver disease. However, the potential role of the ATX-LPA axis in hepatic encephalopathy (HE) remains unclear. Our study aimed to investigate the role of the ATX-LPA signaling pathway in mice with thioacetamide (TAA) induced acute HE. To show the role of the ATX-LPA axis in the context of HE, we first measured the involvement of ATX-LPA in the pathogenesis of TAA-induced acute HE. Then, we compared the potential effects of ATX inhibitor (HA130) on astrocyte responses at in vitro and gut–liver–brain axis at in vivo levels. The inflammatory chemokine (C–C motif) ligand 3 was significantly increased in the hyperammonemic condition and could be prevented by ATX inhibition in astrocytes at in vitro level. Further statistical tests revealed that plasma and tissue pro-inflammatory cytokines were inhibited by HA130 in mice. Furthermore, the stage of HE was significantly improved by HA130. The most surprising result was that HA130 alleviated immune infiltrating cells in the liver and intestine and decreased mucus-secreting cells in the intestine. Further analysis showed that the levels of liver enzymes in serum were significantly decreased in response to ATX inhibition. Surprisingly, our data indicated that HA130 could recover permeabilization of the blood-brain barrier, neuroinflammation, and recognition memory. Besides that, we found that the changes of Interleukin-1 (IL-1) and aquaporin-4 (AQP4) in HE might have a connection with the glymphatic system based on bioinformatics analyses. Taken together, our data showed that the ATX-LPA axis contributes to the pathogenesis of HE and that inhibition of ATX improves HE. Nature Publishing Group UK 2023-08-01 /pmc/articles/PMC10394058/ /pubmed/37528089 http://dx.doi.org/10.1038/s41419-023-06022-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sepehrinezhad, Ali
Shahbazi, Ali
Joghataei, Mohammad Taghi
Larsen, Fin Stolze
Sahab Negah, Sajad
Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
title Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
title_full Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
title_fullStr Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
title_full_unstemmed Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
title_short Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
title_sort inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394058/
https://www.ncbi.nlm.nih.gov/pubmed/37528089
http://dx.doi.org/10.1038/s41419-023-06022-5
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