托非格列净通过 miR-21a 损伤介导的 PPARα 上调,减轻饮食诱导的脂肪肝小鼠的肾脏脂质沉积和炎症反应

IF 1.3 4区 医学 Q4 ENDOCRINOLOGY & METABOLISM
Sae Nishihara, Masahiro Koseki, Katsunao Tanaka, Takashi Omatsu, Ayami Saga, Hiroshi Sawabe, Hiroyasu Inui, Takeshi Okada, Tohru Ohama, Daisuke Okuzaki, Yoshihiro Kamada, Masafumi Ono, Makoto Nishida, Mikio Watanabe, Yasushi Sakata
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引用次数: 0

摘要

我们曾在高脂饮食诱导的脂肪性肝病(SLD)模型中证实了肝脏、心脏和皮肤炎症。然而,该模型中肾脏的分子机制仍不清楚。最近有报道称,SGLT2 抑制剂能改善慢性肾病(CKD)。因此,我们利用该模型来评估托非格列净对肾脏脂质代谢和炎症的影响。给 8-10 周大的雄性 C57Bl/6 小鼠喂食含有 0.015% 托非格列净的高脂/高胆固醇/高蔗糖/胆酸(HF/HC/HS/BA)饮食(Tofo 组)或仅喂食 HF/HC/HS/BA 饮食(SLD 组)。八周后,对血清脂质概况、组织学、脂质含量以及肾脏中的 mRNA/microRNA和蛋白质表达水平进行了检测。与 SLD 组相比,Tofo 组的体重(26.9 ± 0.9 vs. 24.5 ± 1.0 g; p < 0.001)和肾脏重量明显减轻。Tofo 组的肾脏胆固醇(9.1 ± 1.6 vs. 7.5 ± 0.7 mg/g;p <;0.05)和非酯化脂肪酸(NEFA)(12.0 ± 3.0 vs. 8.4 ± 1.5 μEq/g;p <;0.01)显著下降。透射电子显微镜显示,托福组存在较少的脂滴。mRNA测序分析显示,托福组脂肪酸代谢相关基因上调,NFκB信号通路相关基因下调。微RNA测序分析表明,托福组的miR-21a下调,miR-204上调。值得注意的是,已知受 miR-21 负向调控的 PPARα 的表达在托福组显著增加,导致β氧化基因 Acox1 和 Cpt1 在托福组中增强。托非格列净通过调节 PPARα 和 miR-21a 降低了肾脏胆固醇和 NEFA 水平,并改善了炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice

We previously demonstrated hepatic, cardiac, and skin inflammation in a high-fat diet-induced steatotic liver disease (SLD) model. However, the molecular mechanism in the kidneys in this model remains unclear. It has been recently reported that SGLT2 inhibitors improve chronic kidney disease (CKD). Therefore, we used this model to evaluate the effects of tofogliflozin on renal lipid metabolism and inflammation. Male 8–10-week-old C57Bl/6 mice were fed a high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or an HF/HC/HS/BA diet alone (SLD group). After eight weeks, serum lipid profiles, histology, lipid content, and mRNA/microRNA and protein expression levels in the kidney were examined. The Tofo group showed significant reductions in body (26.9 ± 0.9 vs. 24.5 ± 1.0 g; p < 0.001) and kidney weight compared to those of the SLD group. Renal cholesterol (9.1 ± 1.6 vs. 7.5 ± 0.7 mg/g; p < 0.05) and non-esterified fatty acid (NEFA) (12.0 ± 3.0 vs. 8.4 ± 1.5 μEq/g; p < 0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed the presence of fewer lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. MicroRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Notably, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and Cpt1 in the Tofo group. Tofogliflozin decreased renal cholesterol and NEFA levels and improved inflammation through the regulation of PPARα and miR-21a.

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来源期刊
Endocrine journal
Endocrine journal 医学-内分泌学与代谢
CiteScore
4.30
自引率
5.00%
发文量
224
审稿时长
1.5 months
期刊介绍: Endocrine Journal is an open access, peer-reviewed online journal with a long history. This journal publishes peer-reviewed research articles in multifaceted fields of basic, translational and clinical endocrinology. Endocrine Journal provides a chance to exchange your ideas, concepts and scientific observations in any area of recent endocrinology. Manuscripts may be submitted as Original Articles, Notes, Rapid Communications or Review Articles. We have a rapid reviewing and editorial decision system and pay a special attention to our quick, truly scientific and frequently-citable publication. Please go through the link for author guideline.
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