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Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content

Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available s...

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Autores principales: Sasaki, Yusuke, Asahiyama, Masato, Tanaka, Toshiya, Yamamoto, Shogo, Murakami, Kentaro, Kamiya, Wakana, Matsumura, Yoshihiro, Osawa, Tsuyoshi, Anai, Motonobu, Fruchart, Jean-Charles, Aburatani, Hiroyuki, Sakai, Juro, Kodama, Tatsuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210999/
https://www.ncbi.nlm.nih.gov/pubmed/32385406
http://dx.doi.org/10.1038/s41598-020-64902-8
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author Sasaki, Yusuke
Asahiyama, Masato
Tanaka, Toshiya
Yamamoto, Shogo
Murakami, Kentaro
Kamiya, Wakana
Matsumura, Yoshihiro
Osawa, Tsuyoshi
Anai, Motonobu
Fruchart, Jean-Charles
Aburatani, Hiroyuki
Sakai, Juro
Kodama, Tatsuhiko
author_facet Sasaki, Yusuke
Asahiyama, Masato
Tanaka, Toshiya
Yamamoto, Shogo
Murakami, Kentaro
Kamiya, Wakana
Matsumura, Yoshihiro
Osawa, Tsuyoshi
Anai, Motonobu
Fruchart, Jean-Charles
Aburatani, Hiroyuki
Sakai, Juro
Kodama, Tatsuhiko
author_sort Sasaki, Yusuke
collection PubMed
description Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM). A global gene expression analysis indicated that pemafibrate enhances TG hydrolysis and fatty acid β-oxidation as well as re-esterification from dihydroxyacetone 3-phosphate and monoacylglycerol to TG. These changes are accompanied by the induction of genes involved in lipolysis and lipid droplet formation, along with an increased number and reduced size of lipid droplets in pemafibrate-treated livers. Pemafibrate reduced the expression of the cell adhesion molecule Vcam-1, myeloid cell markers, and inflammation- and fibrosis-related genes in STAM mice. Furthermore, pemafibrate significantly reduced VCAM-1 expression induced by high glucose in cultured human umbilical vein endothelial cells. These results suggest that pemafibrate prevents NASH development by reducing myeloid cell recruitment via interactions with liver sinusoidal endothelial cells, without altering hepatic TG accumulation.
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spelling pubmed-72109992020-05-19 Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content Sasaki, Yusuke Asahiyama, Masato Tanaka, Toshiya Yamamoto, Shogo Murakami, Kentaro Kamiya, Wakana Matsumura, Yoshihiro Osawa, Tsuyoshi Anai, Motonobu Fruchart, Jean-Charles Aburatani, Hiroyuki Sakai, Juro Kodama, Tatsuhiko Sci Rep Article Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM). A global gene expression analysis indicated that pemafibrate enhances TG hydrolysis and fatty acid β-oxidation as well as re-esterification from dihydroxyacetone 3-phosphate and monoacylglycerol to TG. These changes are accompanied by the induction of genes involved in lipolysis and lipid droplet formation, along with an increased number and reduced size of lipid droplets in pemafibrate-treated livers. Pemafibrate reduced the expression of the cell adhesion molecule Vcam-1, myeloid cell markers, and inflammation- and fibrosis-related genes in STAM mice. Furthermore, pemafibrate significantly reduced VCAM-1 expression induced by high glucose in cultured human umbilical vein endothelial cells. These results suggest that pemafibrate prevents NASH development by reducing myeloid cell recruitment via interactions with liver sinusoidal endothelial cells, without altering hepatic TG accumulation. Nature Publishing Group UK 2020-05-08 /pmc/articles/PMC7210999/ /pubmed/32385406 http://dx.doi.org/10.1038/s41598-020-64902-8 Text en © The Author(s) 2020 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/.
spellingShingle Article
Sasaki, Yusuke
Asahiyama, Masato
Tanaka, Toshiya
Yamamoto, Shogo
Murakami, Kentaro
Kamiya, Wakana
Matsumura, Yoshihiro
Osawa, Tsuyoshi
Anai, Motonobu
Fruchart, Jean-Charles
Aburatani, Hiroyuki
Sakai, Juro
Kodama, Tatsuhiko
Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
title Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
title_full Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
title_fullStr Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
title_full_unstemmed Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
title_short Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
title_sort pemafibrate, a selective pparα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210999/
https://www.ncbi.nlm.nih.gov/pubmed/32385406
http://dx.doi.org/10.1038/s41598-020-64902-8
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