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

Yusuke Sasaki, Masato Asahiyama, Toshiya Tanaka, Shogo Yamamoto, Kentaro Murakami, Wakana Kamiya, Yoshihiro Matsumura, Tsuyoshi Osawa, Motonobu Anai, Jean Charles Fruchart, Hiroyuki Aburatani, Juro Sakai, Tatsuhiko Kodama

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number7818
JournalScientific reports
Volume10
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

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    Sasaki, Y., Asahiyama, M., Tanaka, T., Yamamoto, S., Murakami, K., Kamiya, W., Matsumura, Y., Osawa, T., Anai, M., Fruchart, J. C., Aburatani, H., Sakai, J., & Kodama, T. (2020). Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Scientific reports, 10(1), [7818]. https://doi.org/10.1038/s41598-020-64902-8