Fine‐Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease

Abstract

Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1‐overexpressing (SIRT oe ) and hepatocyte‐specific SIRT1‐KO (knockout) mice ( SIRT hep–/– ) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24‐norursodeoxycholic acid) was tested in BDL/SIRT oe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice ( Mdr2 –/– ) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro . SIRT oe mice showed exacerbated parenchymal injury whereas SIRT hep–/– mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRT oe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRT hep–/– hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRT oe mice. Interestingly, both SIRT1 overexpression and hepatocyte‐specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine‐tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage.

Protection of hepatocyte mitochondrial function by blueberry juice and probiotics via SIRT1 regulation in non-alcoholic fatty liver disease

“…27 Regulation of SIRT1 expression is essential to protect the liver from cholestatic liver disease. 28 Song et al suggested that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery. 29 Dioscin markedly prevented NAFLD by adjusting lipid metabolism via the SIRT1/AMPK signal pathway, which should be considered as a new therapeutic candidate for NAFLD.…”

Aging and the Biological Response to Liver Injury

“…91 Dysregulation of glycolysis, triglyceride synthesis, and lipid metabolism occurs because of decreased expression of sirtuin, PGC-1α, and lower concentrations of NAD þ . 92 The analysis of senescence markers in aged mice showed upregulation of p16 and downregulation of STIR1 in the liver tissue; interestingly, the latter is known to regulate liver regeneration and bile acid metabolism by modulating farnesoid X receptor. 93 On the contrary, hepatocytes are relatively resistant to telomere shortening, 94 maybe due to the high expression levels of telomerase.…”

Platelet activating factor receptor acts to limit colitis‐induced liver inflammation

“…Previous studies have demonstrated that increases in Sirt1 suppress PAFR expression in platelets and that increases in Sirt1 limits cholestasis 26,27 . To investigate whether Sirt1 was associated with decreased PAFR in colitis‐induced liver inflammation, we measured Sirt1 gene and protein levels in the livers during colitis‐induced inflammation.…”

“…Curiously, in the Huh7 cells, overexpression of PAFR had an additive effect to LPS‐induced Sirt1 increases. This may indicate that downregulation of PAFR is important in fine tuning or restricting Sirt1 responses, which is important in protecting the liver from cholestasis 27 . It is unclear why PAFR protein localizes at the portal triad, comprising of the portal artery, portal vein, and bile duct, 40 during colitis, although this may be driven by localized ischemia caused by endotoxin exposure 49 .…”