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

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.