Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid fed mouse model of cholestasis

Abstract

Sirtuin1 (Sirt1, mammalian homolog of S. Cerevisiae enzyme Sir2) is a transcriptional and transactivational regulator of murine Fxr, which is the primary bile acid (BA) sensor, and critical regulator of BA metabolism in physiological and pathophysiological conditions. Previous studies have suggested compromised Sirt1 expression in rodent models of cholestatic liver injury. We hypothesized that Sirt1 could be potentially targeted to alleviate cholestatic liver injury. In cultured primary human hepatocytes, SIRT1 mRNA was downregulated after GCA treatment, potentially via induction of miR-34a, whereas TUDCA induced SIRT1 expression without affecting miR-34a expression. Sirt1 expression was also significantly downregulated in three mouse models of liver injury (bile duct ligation, 1% cholic acid (CA) fed and the Mdr2 ^−/− mouse). Mice fed CA diet also demonstrated hepatic FXR hyperacetylation and induction of the Jnk/p53 pathway. Mice fed CA diet and concurrently administered the Sirt1 activator; SRT1720 (50mg/kg/day, orally), demonstrated 40% and 45% decrease in plasma ALT and BA levels respectively. SRT1720 increased hepatic BA hydrophilicity by increasing tri- and tetra-hydroxylated and decreasing the di-hydroxylated BA fraction. SRT1720 administration also inhibited hepatic BA synthesis potentially via ileal Fgf15 and Fxr mediated inhibition of Cyp7a1 and Cyp27a1, along with increased hepatic BA hydroxylation in association with Cyp2b10 induction. SRT1720 administration significantly induced renal Mrp2, Mrp4, Pgc1α and Car expression along with ~2 fold increase in urinary BA concentrations.

Conclusion

SRT1720 administration alleviates cholestatic liver injury in mice by increasing hydrophilicity of hepatic BA composition and decreasing plasma BA concentration via increased BA excretion into urine. Thus, use of small molecule activators of Sirt1 presents a novel therapeutic target for cholestatic liver injury.