ENTERAL OBETICHOLIC ACID PREVENTS HEPATIC CHOLESTASIS IN TOTAL PARENTERAL NUTRITION-FED NEONATAL PIGS

Total parenteral nutrition (TPN) is a vital support for neonatal infants with congenital or acquired gastrointestinal (GI) disorders and requiring small bowel resection. An adverse outcome associated with prolonged TPN use is parenteral nutrition associated cholestasis (PNAC). We previously showed that enteral chenodeoxycholic acid (CDCA) treatment reduced PNAC. We hypothesized that the protective effects of CDCA were mediated by modulation of FXR-target genes involved in bile acid homeostasis. The aim of the current study was to compare the physiological effects of a selective FXR agonist, obeticholic acid (OCA) vs CDCA on hepatic bile acid homeostasis in TPN fed piglets. Term, newborn pigs were assigned to receive complete TPN (PN), TPN + enteral CDCA (30 mg/kg), or TPN+enteral OCA (0.5, 5, 15 mg/kg) daily for 19 d. The daily parenteral lipid was Intralipid given at 10 g/kg. Endpoints of PNALD and bile acid homeostasis were measured. We found that, compared to PN pigs, treatment with high dose of OCA (OCA5 and OCA15), but not CDCA and low dose of OCA (OCA0.5), reduced serum PNAC markers including bilirubin, gammaglutamyltransferase (GGT), total bile acid, triglyceride, and very-low-density lipoprotein. Compared to PN, OCA 5 and 15, but not OCA 0.5 or CDCA, reduced the total plasma bile acid concentration by increasing the proportional transfer of hepatic bile acid into the gallbladder, suggesting increased bile flow. TPN-induced ductopenia as measured by percentage of intact bile ducts per portal tract was prevented by OCA suggesting preservation of bile ducts. The major bile acids in plasma were glyco-conjugated forms of CDCA, hyocholic acid and hyodeoxycholic acid. OCA5 and OCA15, but not CDCA, suppressed hepatic expression of CYP7A1, while CYP27A1 and CYP8B1 mRNA remained unchanged. The bile acid detoxification enzyme CYP3A29 mRNA was inhibited by both CDCA and OCA treatments. OCA, but not CDCA upregulated hepatic mRNA involved in hepatobiliary bile acid and bilirubin transport into bile including bile salt export pump (BSEP), multidrug resistance protein 1(MDR1), and multidrug resistance protein 4 (MRP4). OCA5 and OCA15 induced hepatic and ileal FGF19 expression more than CDCA in pigs. We further found that OCA5 and OCA15, but not CDCA, inhibited the hepatic expression of inflammatory marker interleukin-8. Contrary to our previous study, we found that CDCA did not prevent PNAC. We suspect that this was due to the higher lipid load infused. We conclude that enteral OCA is more effective than CDCA in prevention of PNAC via upregulation of FXR-target genes involved in preservation of hepatobiliary transporters and bile duct function. Print