Dysregulation of bile acid homeostasis in parenteral nutrition mouse model

Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved in a variety of liver functions at the mRNA levels. PN increased liver gene expression of Cyp7a1 and markedly decreased that of Cyp8b1, Cyp7b1, Bsep, and Shp. CYP7A1 and CYP8B1 are important for synthesizing the total amount of BAs and regulating the hydrophobicity of BAs, respectively. Consistently, both the levels and the percentages of primary BAs as well as total non-12 alpha-OH BAs increased significantly in the serum of PN mice compared with saline controls, whereas liver BA profiles were largely similar. The expression of several key liver-X receptor-alpha (LXR alpha) target genes involved in lipid synthesis was also increased in PN mouse livers. Retinoid acid-related orphan receptor-alpha (ROR alpha) has been shown to induce the expression of Cyp8b1 and Cyp7b1, as well as to suppress LXR alpha function. Western blot showed significantly reduced nuclear migration of ROR alpha protein in PN mouse livers. This study shows that continuous PN infusion with SOLE in mice leads to dysregulation of BA homeostasis. Alterations of liver ROR alpha signaling in PN mice may be one of the mechanisms implicated in the pathogenesis of PNALD.