The monomer TEC of blueberry improves NASH by augmenting tRF-47-mediated autophagy/pyroptosis signaling pathway

Abstract

Background Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and has no safe and effective drug for treatment. We have previously reported the function of blueberry, but the effective monomer and related molecular mechanism remain unclear. Methods The monomer of blueberry was examined by ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The NASH cell model was constructed by exposing HepG2 cells to free fatty acids. The NASH mouse model was induced by a high-fat diet for 12 weeks. NASH cell and mouse models were treated with different concentrations of blueberry monomers. The molecular mechanism was studied by Oil Red O staining, ELISA, enzyme activity, haematoxylin–eosin (H&E) staining, immunohistochemistry, immunofluorescence, western blot, RNA sequencing, and qRT-PCR. Results We identified one of the main monomer of blueberry as tectorigenin (TEC). Cyanidin-3-O glucoside (C3G) and TEC could significantly inhibit the formation of lipid droplets in steatosis hepatocytes, and the effect of TEC on the formation of lipid droplets was significantly higher than that of C3G. TEC can promote cell proliferation and inhibit the release of inflammatory mediators in NASH cell model. Additionally, TEC administration provided a protective role against high-fat diets induced lipid damage, and suppressed lipid accumulation. In NASH mouse model, TEC can activate autophagy, inhibit pyroptosis and the release of inflammatory mediators. In NASH cell model, TEC inhibited pyroptosis by stimulating autophagy. Then, small RNA sequencing revealed that TEC up-regulated the expression of tRF-47-58ZZJQJYSWRYVMMV5BO (tRF-47). The knockdown of tRF-47 blunted the beneficial effects of TEC on NASH in vitro, including inhibition of autophagy, activation of pyroptosis and release of inflammatory factors. Similarly, suppression of tRF-47 promoted the lipid injury and lipid deposition in vivo. Conclusions These results demonstrated that tRF-47-mediated autophagy and pyroptosis plays a vital role in the function of TEC to treat NASH, suggesting that TEC may be a promising drug for the treatment of NASH.

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Sesamin ameliorates nonalcoholic steatohepatitis through inhibiting hepatocyte pyroptosis in vivo and in vitro

“…Therefore, further research is needed to clarify whether Ses’s anti-pyroptosis effects are associated with the inhibition of the hepatocyte PKCδ/NLRC4 axis caused by its lipid-lowering effects. Second, promoting autophagy may improve NASH by inhibiting pyroptosis ( Zhu et al, 2022 ). Further studies are required to investigate whether Ses’s anti-pyroptosis effects are associated with its ability to induce autophagy ( Tanabe et al, 2011 ).…”

Ginsenoside Rg1 attenuates the NASH phenotype by regulating the miR-375-3p/ATG2B/PTEN-AKT axis to mediate autophagy and pyroptosis

“…The pathogenesis of NASH stays underexplored [26]. NASH is on the whole characterized by immoderate fat deposition in the liver and the dysregulation of lipid metabolism and reactive oxygen species [27,28]. At present, we comprehend that dietary recommendations and bodily workouts are the major techniques of NASH treatment [29], however, we need to discover new objectives from the pathogenesis of NASH, to suggest greater high-quality therapy methods.…”