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A Selective PPARγ modulator, Pemafibrate Suppressed NLRP3 Inflammasome Activation Both in Liver and Heart in a Model of “Steatohepatitis-Related Cardiomyopathy”

ABSTRACT: 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 PPARα 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-1βmRNA. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE175708 | GEO | 2022/02/23

REPOSITORIES: GEO

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Project description:Background: Lamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). Objectives: This study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease. Methods: Consecutive patients with end-stage lamin heart disease (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) undergoing heart transplantation were enrolled. Samples were obtained from left atrium(LA), left ventricle(LV), right atrium(RA), right ventricle(RV) and interventricular septum(IVS). Liquid chromatography combined with mass-spectrometry was used for protein quantification. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if the quantitative difference was 1.5-fold and corrected p-value <0.05 at a false discovery rate of 0.01. Gene ontology(GO) enrichment analysis explored the related biological processes. Results: 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix(ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Conclusion: Lamin heart disease is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses.

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A Selective PPARγ modulator, Pemafibrate Suppressed NLRP3 Inflammasome Activation Both in Liver and Heart in a Model of “Steatohepatitis-Related Cardiomyopathy”

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