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

Kotaro Kanno,Shigeyoshi Saito,Masafumi Ono,Takumi Kawaguchi ,Katsunao Tanaka,Masumi Asaji,Seiko Ide,Makoto Nishida,Tohru Ohama,Haruyuki Inui ,Daisuke Okuzaki,Shizuya Yamashita,Ayami Saga,Takeshi Okada,Toshiji Saibara,Jiuyang Chang,Yinghong Zhu,Tomoaki Higo,Masahiro Koseki,Yasushi Sakata

doi:10.1038/s41598-022-06542-8

Abstract

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.

Highlights

Patients with nonalcoholic fatty liver disease have been reported to have cardiac dysfunction, and appropriate model has not been reported
Lee et al reported that the presence of nonalcoholic fatty liver disease (NAFLD) and the degree of hepatic fibrosis were associated with echocardiographic early diastolic LV filling velocity/peak atrial filling velocity (E/A) ratio and ratio between the E wave velocity from mitral inflow and the E’ velocity (E/e’), which indicate left ventricular (LV) diastolic function[7]
We found free cholesterol accumulation (Fig. 4C), which might be involved in the upregulation of Caspase-1, Asc, and IL-1β and the activation of the NLRP3 inflammasome pathway (Fig. 7)

Summary

Introduction

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. Sequential administration of pemafibrate after the development of steatohepatitis-related cardiomyopathy recovered hepatic fibrosis and cardiac dysfunction. Reports have indicated that the number of patients with nonalcoholic fatty liver disease (NAFLD) is markedly increasing worldwide[1]. Recent studies have demonstrated that patients with NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), have an increased risk of cardiovascular d iseases[2,3,4]. A previous report indicated that another fibrate, fenofibrate, had a protective role against cardiac injury in a porcine myosin-induced rat myocarditis m odel[21], no study has investigated whether pemafibrate might regulate cardiac inflammation or cholesterol metabolism in the heart

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Conclusion