Next Article in Journal
Singular Adult Neural Stem Cells Do Not Exist
Next Article in Special Issue
Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery
Previous Article in Journal
Modes of Viroid Transmission
Previous Article in Special Issue
Potential Therapeutic Effects of PPAR Ligands in Glioblastoma
 
 
Article

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

1
Department of Nuclear Receptor Medicine, Laboratories for Systems Biology and Medicine (LSBM) at the Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
2
Pharmaceutical Division, Kowa Company, Ltd., Tokyo 189-0022, Japan
3
Division of Metabolic Medicine, Laboratories for Systems Biology and Medicine (LSBM) at the Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
4
Division of Integrative Nutriomics and Oncology, Laboratories for Systems Biology and Medicine (LSBM) at the Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
5
R3i Foundation, Picassoplatz 8, 4010 Basel, Switzerland
6
Genome Science Division, Laboratories for Systems Biology and Medicine (LSBM) at the Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan
7
Tohoku University Graduate School of Medicine, Division of Molecular Physiology and Metabolism, Sendai 980-8575, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Kay-Dietrich Wagner and Nicole Wagner
Cells 2022, 11(4), 720; https://doi.org/10.3390/cells11040720
Received: 25 January 2022 / Revised: 14 February 2022 / Accepted: 15 February 2022 / Published: 18 February 2022
(This article belongs to the Special Issue The Role of PPARs in Disease II)
Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia. The combination treatment significantly reduced ballooning degeneration of hepatocytes. RNA-seq analysis suggested that Pema and Tofo combination treatment resulted in an increase in glyceroneogenesis, triglyceride (TG) uptake, lipolysis and liberated fatty acids re-esterification into TG, lipid droplet (LD) formation, and Cidea/Cidec ratio along with an increased number and reduced size and area of LDs. In addition, combination treatment reduced expression levels of endoplasmic reticulum stress-related genes (Ire1a, Grp78, Xbp1, and Phlda3). Pema and Tofo treatment significantly improved survival rates and reduced the number of tumors in the liver compared to the NASH control group. These results suggest that SPPARMα and SGLT2 inhibitor combination therapy has therapeutic potential to prevent NASH-HCC progression. View Full-Text
Keywords: SPPARMα; SGLT2; ballooning; ER stress SPPARMα; SGLT2; ballooning; ER stress
Show Figures

Graphical abstract

MDPI and ACS Style

Murakami, K.; Sasaki, Y.; Asahiyama, M.; Yano, W.; Takizawa, T.; Kamiya, W.; Matsumura, Y.; Anai, M.; Osawa, T.; Fruchart, J.-C.; Fruchart-Najib, J.; Aburatani, H.; Sakai, J.; Kodama, T.; Tanaka, T. Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. Cells 2022, 11, 720. https://doi.org/10.3390/cells11040720

AMA Style

Murakami K, Sasaki Y, Asahiyama M, Yano W, Takizawa T, Kamiya W, Matsumura Y, Anai M, Osawa T, Fruchart J-C, Fruchart-Najib J, Aburatani H, Sakai J, Kodama T, Tanaka T. Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. Cells. 2022; 11(4):720. https://doi.org/10.3390/cells11040720

Chicago/Turabian Style

Murakami, Kentaro, Yusuke Sasaki, Masato Asahiyama, Wataru Yano, Toshiaki Takizawa, Wakana Kamiya, Yoshihiro Matsumura, Motonobu Anai, Tsuyoshi Osawa, Jean-Charles Fruchart, Jamila Fruchart-Najib, Hiroyuki Aburatani, Juro Sakai, Tatsuhiko Kodama, and Toshiya Tanaka. 2022. "Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis" Cells 11, no. 4: 720. https://doi.org/10.3390/cells11040720

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop