GSE175708
A Selective PPAR? modulator, Pemafibrate Suppressed NLRP3 Inflammasome Activation Both in Liver and Heart in a Model of “Steatohepatitis-Related Cardiomyopathy”
It has been recently reported that the patients with non-alcoholic fatty liver diseases (NAFLD) had accompanied with cardiac dysfunction.  However, an animal model of steatohepatitis related cardiomyopathy has not been reported.  In the current study, we have developed a mouse model of steatohepatitis-related cardiomyopathy and examined whether a selective PPARa modulator, pemafibrate would improve both steatohepatitis and cardiomyopathy. C57Bl/6 male mice were fed 1. normal chow diet (C group), 2. high fat/high cholesterol/high sucrose/bile acid diet (N group), or 3. N with pemafibrate 0.1 mg/kg (NP group) for three or eight weeks, respectively.  Cardiac function was evaluated by ultra-high magnetic field 7-Tesla magnetic resonance imaging (7T-MRI).  Even at the eight weeks, we have detected cholesterol crystals, free cholesterol accumulation in liver, followed by macrophage infiltration and fibrosis as wells as activation of NLRP3, caspase-1 and IL-1ßmRNA.  At the same time in heart, the ratio of heart to body was increased in N group compared to C group.  Left ventricular (LV) ejection fraction (LVEF) was moderately decreased in N group compared to C group (50.2±2.8 vs 59.8±2.1, p<0.05).  LV circumferential strain and radial strain are focally attenuated in N group, suggesting the early lesion of myocardial damages.  mRNA expression of Nlrp3, Caspase1 and Il1b were enhanced in N group, followed by increased protein levels of Caspase-1 and Asc.  Rna-sequence analysis revealed that NOD-like receptor and PI3 kinase-AKT pathways were up-regulated, suggesting hypertrophic phenotypes. in N group.  Importantly, NLRP3 inflammasome activation were suppressed both in liver and heart in NP group, suggesting pemafibrate had the beneficial effect on steatohepatitis and cardiomyopathy.  In addition, four week treatment by pemafibrate improved steatohepatitis and cardiomyopathy after development for eight week. We have first developed the animal model of steatohepatitis-related cardiomyopathy, characterized by the activation of NLRP3 inflammasome pathway both in liver and heart.  Steatohepatitis-related cardiomyopathy displayed moderate reduction of LVEF and focal impairment of LV strain by 7T-MRI.  Pemafibrate suppressed steatohepatitis, hepatic fibrosis and cardiomyopathy. Overall design: We compared the three (C, N and NP)goups in duplicates.