The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure.

Anna Maria Czarnecka,Magdalena Zielińska,Krzysztof Milewski,Jan Albrecht

doi:10.3390/ijms21207750

Abstract

Acute liver failure (ALF) leads to neurological symptoms defined as hepatic encephalopathy (HE). Although accumulation of ammonia and neuroinflammation are generally accepted as main contributors to HE pathomechanism, a buildup of bile acids (BA) in the blood is a frequent component of liver injury in HE patients. Recent studies have identified the nuclear farnesoid X receptor (FXR) acting via small heterodimer partner (SHP) as a mediator of BA-induced effects in the brain of ALF animals. The present study investigated the status of the BA–FXR axis in the brain and the liver, including selective changes in pertinent genes in thioacetamide (TAA)-induced ALF in Sprague–Dawley rats. FXR was found in rat neurons, confirming earlier reports for mouse and human brain. BA accumulated in blood but not in the brain tissue. Expression of mRNAs coding for Fxr and Shp was reduced in the hippocampus and of Fxr mRNA also in the cerebellum. Changes in Fxr mRNA levels were not followed by changes in FXR protein. The results leave open the possibility that mobilization of the BA–FXR axis in the brain may not be necessarily pathognomonic to HE but may depend upon ALF-related confounding factors.

Highlights

Hepatic encephalopathy (HE) is a complex neurological syndrome associated with acute or chronic liver failure (ALF or CLF)
Acute liver failure (ALF), which results from fulminant action of hepatotoxins, is a cause of type A HE, a condition invariably manifested by rapid progression of neurotransmission imbalance resulting in pre-coma to coma and by an evolution of brain edema, which is a major cause of death [1]
While ammonia and inflammatory mediators are well documented and probably the major contributors to the neurological manifestations of ALF [2,3], they do not exhaust the list of potential pathogenic factors in HE

Summary

Introduction

Hepatic encephalopathy (HE) is a complex neurological syndrome associated with acute or chronic liver failure (ALF or CLF). Elevation of plasma BA during liver failure leads to the excessive rise in cerebral BA levels in humans and rodents [4,8,9,10] most likely arising in there from the systemic circulation through disrupted brain–blood barrier (BBB) [11]. The presence of the alternative pathway of BA synthesis in the brain [12], along with the widespread distribution of several types of BA receptors in the human and rodent brain [8,13,14] prompts interests of BA signaling in the context of HE-associated neurological dysfunctions

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