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Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

Authors :
Matthew McMillin
Gabriel Frampton
Samir Ashfaq
Stephanie Grant
Matthew A. Quinn
Mario de los Santos
Sharon DeMorrow
Source :
The American journal of pathology. 186(2)
Publication Year :
2015

Abstract

Hepatic encephalopathy is a serious neurological complication of liver failure. Serum bile acids are elevated after liver damage and may disrupt the blood-brain barrier and enter the brain. Our aim was to assess the role of serum bile acids in the neurological complications after acute liver failure. C57Bl/6 or cytochrome p450 7A1 knockout (Cyp7A1(-/-)) mice were fed a control, cholestyramine-containing, or bile acid-containing diet before azoxymethane (AOM)-induced acute liver failure. In parallel, mice were given an intracerebroventricular infusion of farnesoid X receptor (FXR) Vivo-morpholino before AOM injection. Liver damage, neurological decline, and molecular analyses of bile acid signaling were performed. Total bile acid levels were increased in the cortex of AOM-treated mice. Reducing serum bile acids via cholestyramine feeding or using Cyp7A1(-/-) mice reduced bile acid levels and delayed AOM-induced neurological decline, whereas cholic acid or deoxycholic acid feeding worsened AOM-induced neurological decline. The expression of bile acid signaling machinery apical sodium-dependent bile acid transporter, FXR, and small heterodimer partner increased in the frontal cortex, and blocking FXR signaling delayed AOM-induced neurological decline. In conclusion, circulating bile acids may play a pathological role during hepatic encephalopathy, although precisely how they dysregulate normal brain function is unknown. Strategies to minimize serum bile acid concentrations may reduce the severity of neurological complications associated with liver failure.

Details

ISSN :
15252191
Volume :
186
Issue :
2
Database :
OpenAIRE
Journal :
The American journal of pathology
Accession number :
edsair.doi.dedup.....8ca8f0371286460b0885abdb44325db6