Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition–associated cholestasis in mice

Abstract

after first online publication: In the Abstracts "dextran sodium sulfate" was corrected to "dextran sulfate sodium"; In the caption for Figure 7D, the words "GW4064 and" and "untreated and" appeared in the published article and are now removed. We apologize to the authors and our readers for these errors.

Interrupting tumor necrosis factor–alpha signaling prevents parenteral nutrition–associated cholestasis in mice

“…12,14 Recently, a new model of PNAC has been developed that combines 75% intestinal resection and PN in 7-10 day old piglets. 44 In agreement with our murine studies, in this model gut Nr1h4 (FXR) is suppressed, 17 whereas in the DSS-PN/Inflix group, we find a direct correlation between decreased hepatic expression of Cyp7a1 with elevated hepatic Fgfr4 expression, in the piglet model of complete ileal and ileocecal valve resection, hepatic Cyp7a1 expression was increased corresponding to decreased gut FGF19 expression, the latter presumably the result of resection of the ileum (which is where FGF19 is expressed) and absence of enteral feedings. It should be noted that in most infants and adults with SBS, absence of the ileum is rare.…”

“…14 Antibiotic suppression of intestinal microbiota, abrogation of macrophage recruitment, activation of FXR, as well as blockade of LPS or IL1 signaling in the mouse model all attenuated PNAC and restored Abcc2 and Abcb11 transcription. 12,14,17 Here, we mechanistically linked inflammatory signals with cholestasis in the PNAC mouse model and demonstrate that TNFαα directly suppressed expression of hepatocellular bile transporters Abcc2, Abcb11, Abcg5, and Abcg8 in vivo and in vitro in both human hepatoma cell lines and primary mouse hepatocytes. Genetic or pharmacological blockade of TNF signaling protected mice from PNAC through preventing bile transporter downregulation.…”

“…Mechanistically, we showed that hepatocellular NF‐κB reduces FXR transcription and signaling which, in turn, suppresses expression of hepatic bile acid and sterol transporters and promotes hepatocyte accumulation of toxic bile acids and phytosterols 14 . Antibiotic suppression of intestinal microbiota, abrogation of macrophage recruitment, activation of FXR, as well as blockade of LPS or IL1 signaling in the mouse model all attenuated PNAC and restored Abcc2 and Abcb11 transcription 12,14,17 …”

“…9,12,14,15 In this model, liver injury and cholestasis are associated with intestinal dysbiosis, increased intestinal permeability, increased LPS absorption into the portal vein, and hepatic macrophage activation with increased transcription of tumor necrosis factor-alpha signaling (TNFα). 12,14,16 On a molecular level, macrophage activation and cholestasis in mice was associated with reduced hepatic transcription of Farnesoid X Receptor (Fxr [encoded by Nr1h4]), 17 Liver receptor homolog 1 (Lrh1 [encoded by Nr5a2]), 15 and canalicular transporters for bile salts (bile salt export pump [BSEP] encoded by Abcb11), conjugated bilirubin (multidrug resistance-associated protein 2 encoded by Abcc2), and plant sterols (sterolin 1 and 2, encoded by Abcg5/g8). 9 These findings mirror many of those found in piglet models of PNAC 18,19 as well as those reported in children with PNAC and IFALD 20 who showed histologic and molecular evidence of liver inflammation.…”

Liver PP2A-Cα Protects From Parenteral Nutrition-associated Hepatic Steatosis

“…33,34 Available studies support the hypothesis that altered FXR signaling is important in the onset of parenteral nutritionassociated cholestasis. 35,36 Moreover, serum FGF19 concentration was associated with hepatic portal inflammatory and fibrotic liver changes in patients with pediatric intestinal failure. 6 Our proteomic results indicated that FXRa (Nr1h4, foldchange ¼ 0.76) was downregulated in patients with PNAHS (Supplementary Data 1), and cholesterol 7a-hydroxylase (CYP7A1; fold-change ¼ 3.08) and sterol 12a-hydroxylase (CYP8B1; fold-change ¼ 1.52), which are the rate-limiting enzymes in the conversion of cholesterol to primary bile acids, were strongly upregulated in patients with PNAHS (Supplementary Data 1).…”