Depletion of S-adenosylmethionine induced by arsenic exposure is involved in liver injury of rat through perturbing histone H3K36 trimethylation dependent bile acid metabolism.

Long-term exposure to arsenic, a common environmental pollutant, can induce various types of liver injury, but the mechanism and treatment measures remain unclear. This study constructed a rat model of arsenic-induced liver injury, with methyl group donor S -adenosylmethionine (SAM) supplementation and Rosa roxburghii Tratt juice intervention, to explore the epigenetic mechanism and intervention method of arsenic-induced liver injury from the perspective of hepatic bile acid metabolism. The results showed that arsenic exposure induced the accumulation of total bile acids (TBA) in the liver and serum of rats, and the abnormalities in liver function and liver histopathology. Arsenic reduced histone H3K36 trimethylation (H3K36me3) in the liver via consuming methyl group donor SAM. The reduction of H3K36me3 was involved in arsenic-induced bile acid accumulation by inhibiting the transcription of negative feedback regulators Fxr and Fgfr4 for hepatic bile acid synthesis. SAM supplementation reversed arsenic-induced bile acid accumulation and liver injury by reactivating H3k36me3-dependent transcription of Fxr and Fgfr4. Moreover, this study found that Rosa roxburghii Tratt juice could rescue arsenic-induced SAM consumption, recover H3K36me3-dependent negative feedback regulation of hepatic bile acid synthesis, and alleviate arsenic-induced bile acid accumulation and liver injury. In conclusion, arsenic exposure perturbed H3K36me3-dependent hepatic bile acid metabolism via depleting SAM, thereby inducing hepatic bile acid accumulation and liver injury, which was ameliorated by the supporting effect of Rosa roxburghii Tratt juice on SAM. This study contributes to understanding the mechanism of arsenic-induced liver injury from the perspective of SAM-dependent epigenetics, providing new insight into its prevention and treatment. Arsenic exposure consumes methyl group donor SAM, reducing histone H3K36 trimethylation (H3K36me3) levels and inhibiting H3K36me3-dependent transcriptional activation of negative feedback regulators Fxr and Fgfr4 for hepatic bile acid synthesis, thereby inducing bile acid accumulation and subsequently liver injury by promoting bile acid synthesis. Rosa roxburghii Tratt blocks this process by rescuing arsenic-induced consumption of SAM. [Display omitted]. • Arsenic-induced SAM depletion causes bile acid disorder and liver injury. • Arsenic-induced SAM depletion inhibits epigenetic dependent bile acid metabolism. • Rosa roxburghii Tratt alleviates arsenic-induced bile acid disorder and liver injury. • Rosa roxburghii Tratt rescues SAM depletion and aberrational epigenetic regulation. [ABSTRACT FROM AUTHOR]