Activation of TRPA1 prevents metabolic dysfunction-associated steatotic liver disease in diet-induced obese mice through stimulating the AMPK/CPT1A signaling pathway.

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Dan Wang, Sen Liu, Jindong Wan, Shichao Chen, Kaige Feng, Jixin Hou, Yi Yang, Peijian Wang
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Abstract

Mitochondrial dysfunction plays an important role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Transient receptor potential ankyrin-1 (TRPA1) activation improves mitochondrial dysfunction in a variety of cells. The present study tested the effects of Trpa1 knockout and activation in diet-induced MASLD in mice and palmitate-induced lipid deposition in HepG2 cells. Mice were fed with a high-fat diet (HFD) for 24 weeks to establish the animal model of MASLD. TRPA1 was downregulated in the liver of mice with MASLD and in HepG2 cells with palmitate-treated steatosis. Compared with HFD-fed wild-type mice, Trpa1-/- mice on HFD demonstrated exacerbated lipid deposition and mitochondrial damage in hepatocytes. AMP-activated protein kinase (AMPK) and carnitine palmitoyl transferase 1 A (CPT1A) in the liver were downregulated by HFD and to a greater extent in Trpa1-/- mice. Similarly, knockdown of Trpa1 worsened palmitate-induced lipid accumulation, mitochondrial morphological damage, mitochondrial ATP reduction and dysfunction, and downregulation of AMPK and CPT1A in HepG2 cells. Oral administration of cinnamaldehyde significantly reduced lipid deposition and improved mitochondrial damage in hepatocytes, which were abolished by HC030031, a TRPA1 antagonist. In HepG2 cells, cinnamaldehyde remarkably attenuated palmitate-induced lipid accumulation, mitochondrial damage, ATP reduction, and mitochondrial dysfunction, which were blunted by HC030031. Cinnamaldehyde reversed downregulation of AMPK and CPT1A in the liver of HFD-fed mice and palmitate-treated HepG2 cells through activating TRPA1. In conclusion, these findings suggest that the downregulation of TRPA1 may be involved in the pathogenesis of MASLD and activation of TRPA1 holds potential in the prevention and treatment of MASLD.

激活TRPA1可通过刺激AMPK/CPT1A信号通路,预防饮食诱导的肥胖小鼠代谢功能障碍相关的脂肪变性肝病。
线粒体功能障碍在代谢功能障碍相关脂肪变性肝病(MASLD)的发病机制中起重要作用。瞬时受体电位锚蛋白-1 (TRPA1)激活可改善多种细胞的线粒体功能障碍。本研究测试了Trpa1敲除和激活在饮食诱导的小鼠MASLD和棕榈酸诱导的HepG2细胞脂质沉积中的作用。采用高脂饲料(HFD)喂养24周,建立MASLD动物模型。TRPA1在MASLD小鼠和棕榈酸处理脂肪变性HepG2细胞的肝脏中下调。与HFD喂养的野生型小鼠相比,HFD喂养的Trpa1-/-小鼠肝细胞脂质沉积和线粒体损伤加剧。肝脏中amp活化的蛋白激酶(AMPK)和肉碱棕榈酰转移酶1a (CPT1A)在Trpa1-/-小鼠中被HFD下调,且在更大程度上下调。同样,敲低Trpa1会加重棕榈酸诱导的HepG2细胞脂质积累、线粒体形态损伤、线粒体ATP减少和功能障碍以及AMPK和CPT1A的下调。口服肉桂醛可显著减少肝细胞脂质沉积,改善线粒体损伤,而TRPA1拮抗剂HC030031可消除这一作用。在HepG2细胞中,肉桂醛显著减弱棕榈酸诱导的脂质积累、线粒体损伤、ATP减少和线粒体功能障碍,而HC030031可以减弱这些作用。肉桂醛通过激活TRPA1逆转hfd喂养小鼠和棕榈酸处理的HepG2细胞中AMPK和CPT1A的下调。综上所述,这些发现提示TRPA1的下调可能参与了MASLD的发病机制,激活TRPA1在MASLD的预防和治疗中具有潜在的作用。
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来源期刊
Journal of physiology and biochemistry
Journal of physiology and biochemistry 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
86
审稿时长
6-12 weeks
期刊介绍: The Journal of Physiology and Biochemistry publishes original research articles and reviews describing relevant new observations on molecular, biochemical and cellular mechanisms involved in human physiology. All areas of the physiology are covered. Special emphasis is placed on the integration of those levels in the whole-organism. The Journal of Physiology and Biochemistry also welcomes articles on molecular nutrition and metabolism studies, and works related to the genomic or proteomic bases of the physiological functions. Descriptive manuscripts about physiological/biochemical processes or clinical manuscripts will not be considered. The journal will not accept manuscripts testing effects of animal or plant extracts.
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