Activation of TRPA1 prevents metabolic dysfunction-associated steatotic liver disease in diet-induced obese mice through stimulating the AMPK/CPT1A signaling pathway.
Dan Wang, Sen Liu, Jindong Wan, Shichao Chen, Kaige Feng, Jixin Hou, Yi Yang, Peijian Wang
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引用次数: 0
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.
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.