Abstract
Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.
Highlights
In surgical practice, the ability of the liver to regenerate is exploited to enable safe liver resection and transplantation
Pilot experiments showed that obstructive cholestasis following reversible bile duct ligation (rBDL) considerably impairs liver regeneration after PHx, whereas the effects of simple steatosis or combined cholestasis and steatosis were less pronounced or even absent (Fig. S2)
It was explored whether the Fxr agonist obeticholic acid (OCA) could improve liver regeneration in rats with obstructive cholestasis
Summary
The ability of the liver to regenerate is exploited to enable safe liver resection and transplantation. The poor regenerative capacity of cholestatic livers has spawned invasive procedures such as preoperative biliary drainage and portal vein embolization (PVE) to respectively relieve cholestasis and increase future remnant liver size prior to resection. The recent clinical evaluation of the FXR agonist obeticholic acid (OCA) for treatment of primary biliary cirrhosis[12] has generated promising results that led to marketing approval of OCA for treating patients non-responsive to first line treatment with UDCA. OCA has not yet been tested in the context of human liver regeneration or in preclinical studies on the regeneration of pre-damaged livers after PHx. Using a rat model of reversible obstructive cholestasis and PHx, we show that OCA treatment triggers ileal Fgf[15] expression and induces liver growth prior to resection. Liver regeneration after PHx was reduced in OCA-treated rats, possibly due to the expansion of liver size prior to PHx
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