Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model
Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model
复制标题
选择性PPARα调节剂、钠-葡萄糖协同转运蛋白2抑制剂和他汀类药物对青鳉非酒精性脂肪肝模型心肌形态的影响
DOI：
10.1016/j.bbrc.2022.07.117
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发表时间：
2022
影响因子：
3.1
通讯作者：
Terai Shuji
中科院分区：
文献类型：
--
作者：
Ohkoshi-Yamada Marina;Kamimura Kenya;Kimura Atsushi;Tanaka Yuto;Nagayama Itsuo;Yakubo Shunta;Abe Hiroyuki;Yokoo Takeshi;Sakamaki Akira;Kamimura Hiroteru;Terai Shuji
目的：非酒精性脂肪性肝病（NAFLD）与代谢失调相关，并与各种心血管并发症相关，常导致预后不良。为了制定NAFLD的标准治疗方法，并迫切解决其并发症，本研究旨在探讨NAFLD相关心脏病的机制以及针对各种代谢途径的药物的治疗效果。方法采用高脂饮食诱导的NAFLD medaka模型，探讨NAFLD相关心脏病的发病机制。以时间依赖性的方式评估心肌的大体结构、组织学和炎症变化。此外，还评估了用于NAFLD治疗的药物的治疗效果，包括选择性过氧化物酶体增殖物激活受体α调节剂（SPPARMα, pemafbrate），钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂（tofogliflozin）和他汀（pitavastatin），以及它们对心脏病理的影响。为了确定治疗效果的机制，通过全转录组测序分析评估了与肝脏炎症相关的基因表达。结果nafld相关性心脏损伤鱼表现为心肌细胞肥大，导致心肌肥大。这种形态学变化是由包括巨噬细胞、CD4 -和cd8阳性淋巴细胞在内的炎症细胞在心壁的浸润以及心肌细胞中转化生长因子β 1的表达引起的。此外，鱼的肝脏有衰老相关分泌表型相关基因的上调表达。使用培马颤动、tofogliflozin和pitavastatin治疗可减少这些变化，从而减少心肌病。结论nafld相关的心脏病是由衰老相关的分泌表型诱导的心壁炎症活动导致心肌肥大引起的。此外，在medaka NAFLD模型中，SPPARMα、SGLT2抑制剂和他汀类药物对NAFLD相关心脏病的影响是明显的。
ObjectiveNonalcoholic 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.MethodsTo 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.ResultsThe 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.ConclusionOur 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.