title: Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.
abstract: The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Kessoku
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomeno
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Imajo
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoneda
authors.affiliation: Department of Pharmacology Research, Tokyo New Drug Research Laboratories, Kowa Co. Ltd., Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takizawa
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.affiliation: Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D015415:Biomarkers; D001706:Biopsy; D002087:Butyrates / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012377:Rodentia; D012720:Severity of Illness Index; D000071247:Uncoupling Protein 3 / Q000235:genetics / Q000378:metabolism
chemical_list: C540740:(R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid; D001583:Benzoxazoles; D015415:Biomarkers; D002087:Butyrates; D047493:PPAR alpha; D000071247:Uncoupling Protein 3