Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Embelin improves alcoholic steatohepatitis in alcohol-associated liver disease via ATF6-mediated P2X7r-NLRP3 signaling pathway.
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Zhang Jin-Jin, Zhong Jiang-Tao, Wang Wan-Ling, Wang Si-Ying, Guo Xin, Sun Hai-Ming, Song Jian
Аннотация
BACKGROUND: Alcohol-associated liver disease (ALD) manifests with impaired lipid metabolism and inflammation within the liver. Embelin (EB), a natural para-benzoquinone compound derived from the Embelia ribes Burm.f. has several pharmacological properties.
OBJECTIVE: This research examines how EB influences the inflammatory milieu of the liver in ALD.
METHODS: In vivo, we created an ALD model by subjecting mice to the Lieber-DeCarli diet for ten days, supplemented by a solitary binge, and subsequent ATF6 silencing. We employed RNA sequencing to analyze the ALD-related signaling pathways. In vitro experiments involved treating AML12 with EB and ethanol, and administering a siRNA-ATF6 to HepG2 cells. We investigated the ATF6 and P2 × 7r promoter interaction through a dual-luciferase assay. Mouse bone marrow-derived macrophages (BMDMs) were also treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP) and EB to produce a conditioned medium.
RESULTS: EB effectively mitigated lipid synthesis and the formation of neutrophil extracellular traps (NETs) during ALD. RNA sequencing revealed significant alterations in the ATF6/NOD-like receptor pathway in alcohol-induced mice. EB up-regulated ATF6 while down-regulating P2 × 7r-NLRP3 and its target genes. shRNA-mediated ATF6 knockdown markedly increased P2 × 7r protein and mRNA levels in mouse livers and exacerbated lipid accumulation. The absence of ATF6 in hepatocytes impaired the inhibitory effect of EB on the P2 × 7r-NLRP3 pathway. It was demonstrated that ATF6 directly binds to the P2 × 7r promoter. Moreover, EB reduced pyroptosis in BMDMs, thereby diminishing the inflammatory response.
CONCLUSIONS: These findings suggest that EB ameliorates alcoholic steatohepatitis (ASH) by modulating the ATF6-P2 × 7r/NLRP3 signaling pathway in ALD. EB might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for alcoholic liver disease.
OBJECTIVE: This research examines how EB influences the inflammatory milieu of the liver in ALD.
METHODS: In vivo, we created an ALD model by subjecting mice to the Lieber-DeCarli diet for ten days, supplemented by a solitary binge, and subsequent ATF6 silencing. We employed RNA sequencing to analyze the ALD-related signaling pathways. In vitro experiments involved treating AML12 with EB and ethanol, and administering a siRNA-ATF6 to HepG2 cells. We investigated the ATF6 and P2 × 7r promoter interaction through a dual-luciferase assay. Mouse bone marrow-derived macrophages (BMDMs) were also treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP) and EB to produce a conditioned medium.
RESULTS: EB effectively mitigated lipid synthesis and the formation of neutrophil extracellular traps (NETs) during ALD. RNA sequencing revealed significant alterations in the ATF6/NOD-like receptor pathway in alcohol-induced mice. EB up-regulated ATF6 while down-regulating P2 × 7r-NLRP3 and its target genes. shRNA-mediated ATF6 knockdown markedly increased P2 × 7r protein and mRNA levels in mouse livers and exacerbated lipid accumulation. The absence of ATF6 in hepatocytes impaired the inhibitory effect of EB on the P2 × 7r-NLRP3 pathway. It was demonstrated that ATF6 directly binds to the P2 × 7r promoter. Moreover, EB reduced pyroptosis in BMDMs, thereby diminishing the inflammatory response.
CONCLUSIONS: These findings suggest that EB ameliorates alcoholic steatohepatitis (ASH) by modulating the ATF6-P2 × 7r/NLRP3 signaling pathway in ALD. EB might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for alcoholic liver disease.