Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model

Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways.To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis.The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy.Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.