ARS | Publication request: Differential molecular regulation of bile acid homeostasis by soy lipid induced phytosterolemia and fish oil lipid emulsions in TPN-fed preterm pigs

Submitted to: Gastroenterology
Publication Type: Abstract Only
Publication Acceptance Date: June 12, 2012
Publication Date: July 12, 2012
Citation: Ng, K., Vlaardingerbroek, H., Stoll, B., Van Goudoever, J., Kluijtmans, L., Olutoye, O., Burrin, D.G. 2012. Differential molecular regulation of bile acid homeostasis by soy lipid induced phytosterolemia and fish oil lipid emulsions in TPN-fed preterm pigs [abstract]. Gastroenterology. 142(5):S-925(suppl. 1).

Technical Abstract: Prolonged total parenteral nutrition (PN) may lead to cholestasis and liver disease (PNALD). The soybean oil-based lipid emulsion (Intralipid) and its constituent phytosterols have been implicated in PNALD. Phytosterols may induce cholestasis by antagonism of the nuclear bile-acid receptor, FXR, leading to increased synthesis and suppressed hepatocyte export of bile acids into bile. Clinical studies in PNALD patients show that the fish oil-based lipid emulsion (Omegaven), which is essentially devoid of phytosterols, can reverse cholestatic markers. We investigated the serum and hepatic tissue bile acid, phytosterol levels, and FXR target genes involved in bile acid homeostasis in TPN-fed preterm piglets given three different lipid emulsions. Preterm piglets were assigned to receive 14 days of either 1) Enteral diet (EN); 2) TPN + Intralipid (100% soybean oil)(IL); 3) TPN + Omegaven (100% fish oil)(OV); or 4) TPN + SMOF (30% soybean, 30% coconut, 25% olive, and 15% fish oil). Serum total bilirubin, bile acids, and GGT were markedly higher (P<0.05) in IL vs. EN pigs, but were lower in OV and SMOF vs. IL. Liver tissue bile acid levels were higher (P<0.05) in IL and OV pigs vs. EN and SMOF pigs. However, IL pigs tended to have a higher liver tissue bile acid level compared to OV pigs. Serum total phytosterol (beta-sitosterol, campesterol, stigmasterol) levels were significantly higher in IL (65 uM) vs. SMOF (21 uM), but barely detectable in OV (1.7 uM) pigs, reflecting the respective composition in the emulsions. These findings support the hypothesis that phytosterolemia leads to disruption of bile acid homeostasis and cholestasis, but this effect may be dose-dependent. FXR, CYP7A1, and BSEP expression were lower (P<0.05) and CYP27A1 expression tended to be lower in the three TPN groups vs. the EN group. However, among the TPN groups, CYP7A1 expression was also lowest (P<0.05) in OV pigs vs. the IL and SMOF pigs. SHP expression was not different among the groups. Importantly, OST-alpha expression was 6-fold higher (P<0.05) in the IL but marginally increased in OV and SMOF vs. EN pigs. In contrast, NTCP expression tended to be lower in all TPN groups vs. the EN group. These findings suggest that TPN decreases FXR-dependent synthesis and export of hepatocyte bile acids into bile. The net result of TPN is greater accumulation of hepatocyte bile acids in IL vs. OV and SMOF, which triggers a compensatory up-regulation of bile acid export into the systemic circulation and biliary injury. Phytosterolemia induced by lipid emulsions produces a dose-dependent cholestatic phenotype, which is most severe with Intralipid. FXR and its target genes are suppressed by all three parenteral lipid emulsions, suggesting that the beneficial effects of fish oil may occur via post-translational mechanisms or FXR-independent pathways.