Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in mice.
ATP Binding Cassette Transporter, Subfamily B, Member 11
/ genetics
ATP Binding Cassette Transporter, Subfamily G, Member 5
/ genetics
ATP Binding Cassette Transporter, Subfamily G, Member 8
/ genetics
Animals
Bile Acids and Salts
/ blood
Cholestasis
/ etiology
Gene Expression
/ drug effects
Gene Expression Regulation
/ drug effects
Hepatocytes
/ metabolism
Interleukin-1beta
/ pharmacology
Intestinal Diseases
/ chemically induced
Isoxazoles
/ pharmacology
Lipoproteins
/ genetics
Liver Diseases
/ etiology
Macrophage Activation
/ drug effects
Macrophages
/ pathology
Male
Mice
Mice, Inbred C57BL
Multidrug Resistance-Associated Protein 2
/ genetics
Multidrug Resistance-Associated Proteins
/ genetics
Parenteral Nutrition
/ adverse effects
RNA, Messenger
/ metabolism
Receptors, Cytoplasmic and Nuclear
/ agonists
Signal Transduction
/ drug effects
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
13
07
2021
received:
20
11
2020
accepted:
26
07
2021
pubmed:
14
8
2021
medline:
3
3
2022
entrez:
13
8
2021
Statut:
ppublish
Résumé
Parenteral nutrition (PN)-associated cholestasis (PNAC) complicates the care of patients with intestinal failure. In PNAC, phytosterol containing PN synergizes with intestinal injury and IL-1β derived from activated hepatic macrophages to suppress hepatocyte farnesoid X receptor (FXR) signaling and promote PNAC. We hypothesized that pharmacological activation of FXR would prevent PNAC in a mouse model. To induce PNAC, male C57BL/6 mice were subjected to intestinal injury (2% dextran sulfate sodium [DSS] for 4 days) followed by central venous catheterization and 14-day infusion of PN with or without the FXR agonist GW4064. Following sacrifice, hepatocellular injury, inflammation, and biliary and sterol transporter expression were determined. GW4064 (30 mg/kg/day) added to PN on days 4-14 prevented hepatic injury and cholestasis; reversed the suppressed mRNA expression of nuclear receptor subfamily 1, group H, member 4 (Nr1h4)/FXR, ATP-binding cassette subfamily B member 11 (Abcb11)/bile salt export pump, ATP-binding cassette subfamily C member 2 (Abcc2), ATP binding cassette subfamily B member 4(Abcb4), and ATP-binding cassette subfamily G members 5/8(Abcg5/8); and normalized serum bile acids. Chromatin immunoprecipitation of liver showed that GW4064 increased FXR binding to the Abcb11 promoter. Furthermore, GW4064 prevented DSS-PN-induced hepatic macrophage accumulation, hepatic expression of genes associated with macrophage recruitment and activation (ll-1b, C-C motif chemokine receptor 2, integrin subunit alpha M, lymphocyte antigen 6 complex locus C), and hepatic macrophage cytokine transcription in response to lipopolysaccharide in vitro. In primary mouse hepatocytes, GW4064 activated transcription of FXR canonical targets, irrespective of IL-1β exposure. Intestinal inflammation and ileal mRNAs (Nr1h4, Fgf15, and organic solute transporter alpha) were not different among groups, supporting a liver-specific effect of GW4064 in this model. GW4064 prevents PNAC in mice through restoration of hepatic FXR signaling, resulting in increased expression of canalicular bile and of sterol and phospholipid transporters and suppression of macrophage recruitment and activation. These data support augmenting FXR activity as a therapeutic strategy to alleviate or prevent PNAC.
Sections du résumé
BACKGROUND AND AIMS
Parenteral nutrition (PN)-associated cholestasis (PNAC) complicates the care of patients with intestinal failure. In PNAC, phytosterol containing PN synergizes with intestinal injury and IL-1β derived from activated hepatic macrophages to suppress hepatocyte farnesoid X receptor (FXR) signaling and promote PNAC. We hypothesized that pharmacological activation of FXR would prevent PNAC in a mouse model.
APPROACH AND RESULTS
To induce PNAC, male C57BL/6 mice were subjected to intestinal injury (2% dextran sulfate sodium [DSS] for 4 days) followed by central venous catheterization and 14-day infusion of PN with or without the FXR agonist GW4064. Following sacrifice, hepatocellular injury, inflammation, and biliary and sterol transporter expression were determined. GW4064 (30 mg/kg/day) added to PN on days 4-14 prevented hepatic injury and cholestasis; reversed the suppressed mRNA expression of nuclear receptor subfamily 1, group H, member 4 (Nr1h4)/FXR, ATP-binding cassette subfamily B member 11 (Abcb11)/bile salt export pump, ATP-binding cassette subfamily C member 2 (Abcc2), ATP binding cassette subfamily B member 4(Abcb4), and ATP-binding cassette subfamily G members 5/8(Abcg5/8); and normalized serum bile acids. Chromatin immunoprecipitation of liver showed that GW4064 increased FXR binding to the Abcb11 promoter. Furthermore, GW4064 prevented DSS-PN-induced hepatic macrophage accumulation, hepatic expression of genes associated with macrophage recruitment and activation (ll-1b, C-C motif chemokine receptor 2, integrin subunit alpha M, lymphocyte antigen 6 complex locus C), and hepatic macrophage cytokine transcription in response to lipopolysaccharide in vitro. In primary mouse hepatocytes, GW4064 activated transcription of FXR canonical targets, irrespective of IL-1β exposure. Intestinal inflammation and ileal mRNAs (Nr1h4, Fgf15, and organic solute transporter alpha) were not different among groups, supporting a liver-specific effect of GW4064 in this model.
CONCLUSIONS
GW4064 prevents PNAC in mice through restoration of hepatic FXR signaling, resulting in increased expression of canalicular bile and of sterol and phospholipid transporters and suppression of macrophage recruitment and activation. These data support augmenting FXR activity as a therapeutic strategy to alleviate or prevent PNAC.
Identifiants
pubmed: 34387888
doi: 10.1002/hep.32101
pii: 01515467-202202000-00006
doi:
Substances chimiques
ABCG5 protein, mouse
0
ABCG8 protein, mouse
0
ATP Binding Cassette Transporter, Subfamily B, Member 11
0
ATP Binding Cassette Transporter, Subfamily G, Member 5
0
ATP Binding Cassette Transporter, Subfamily G, Member 8
0
Abcb11 protein, mouse
0
Abcc4 protein, mouse
0
Bile Acids and Salts
0
IL1B protein, mouse
0
Interleukin-1beta
0
Isoxazoles
0
Lipoproteins
0
Multidrug Resistance-Associated Protein 2
0
Multidrug Resistance-Associated Proteins
0
RNA, Messenger
0
Receptors, Cytoplasmic and Nuclear
0
farnesoid X-activated receptor
0C5V0MRU6P
GW 4064
SR225WUZ0H
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
252-265Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR002535
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK067009
Pays : United States
Informations de copyright
© 2021 by the American Association for the Study of Liver Diseases.
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