Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy

• Published in: Scientific reports 2022-02, Vol.12 (1), p.2996-17, Article 2996
• Main Authors: Kanno, Kotaro, Koseki, Masahiro, Chang, Jiuyang, Saga, Ayami, Inui, Hiroyasu, Okada, Takeshi, Tanaka, Katsunao, Asaji, Masumi, Zhu, Yinghong, Ide, Seiko, Saito, Shigeyoshi, Higo, Tomoaki, Okuzaki, Daisuke, Ohama, Tohru, Nishida, Makoto, Kamada, Yoshihiro, Ono, Masafumi, Saibara, Toshiji, Yamashita, Shizuya, Sakata, Yasushi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 692/4017; 692/4019; 692/4020; 692/499; AKT protein; Animals; Benzoxazoles - administration & dosage; Benzoxazoles - pharmacology; Butyrates - administration & dosage; Butyrates - pharmacology; Cardiomyopathies - drug therapy; Cardiomyopathies - etiology; Cardiomyopathies - metabolism; Cardiomyopathy; Caspase-1; Cholesterol; Crystals; Diet; Diet, High-Fat - adverse effects; Dietary Carbohydrates - adverse effects; Disease Models, Animal; Fatty liver; Fibrosis; Gene expression; Gene Expression - drug effects; Gene Expression - genetics; High cholesterol diet; High fat diet; Humanities and Social Sciences; Hypertrophy; IL-1β; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Liver; Liver - metabolism; Liver diseases; Macrophages; Magnetic fields; Magnetic resonance imaging; Male; Mice; Mice, Inbred C57BL; mRNA; multidisciplinary; Myocardium - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Science; Science (multidisciplinary); Steatosis; Sucrose; Ventricle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-06542-8

Although patients with nonalcoholic fatty liver disease have been reported to have cardiac dysfunction, and appropriate model has not been reported. We established a novel mouse model of diet-induced steatohepatitis-related cardiomyopathy and evaluated the effect of pemafibrate. C57Bl/6 male mice were fed a (1) chow diet (C), (2) high-fat, high-cholesterol, high-sucrose, bile acid diet (NASH diet; N), or (3) N with pemafibrate 0.1 mg/kg (NP) for 8 weeks. In the liver, macrophage infiltration and fibrosis in the liver was observed in the N group compared to the C group, suggesting steatohepatitis. Free cholesterol accumulated, and cholesterol crystals were observed. In the heart, free cholesterol similarly accumulated and concentric hypertrophy was observed. Ultrahigh magnetic field magnetic resonance imaging revealed that the left ventricular (LV) ejection fraction (EF) was attenuated and LV strain was focally impaired. RNA sequencing demonstrated that the NOD-like receptor and PI3 kinase-Akt pathways were enhanced. mRNA and protein expression of inflammasome-related genes, such as Caspase-1, NLRP3, and IL-1β, were upregulated in both the liver and heart. In the NP compared to the N group, steatohepatitis, hepatic steatosis, and cardiac dysfunction were suppressed. Sequential administration of pemafibrate after the development of steatohepatitis-related cardiomyopathy recovered hepatic fibrosis and cardiac dysfunction.