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Role of Bile Acids in Liver Injury and Regeneration following Acetaminophen Overdose
Bharat Bhushan, Prachi Borude, Genea Edwards, Chad Walesky, Joshua Cleveland, Feng Li, Xiaochao Ma, and Udayan Apte
From the Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
Acetaminophen (APAP) overdose is the foremost cause of acute liver failure (ALF) in the US contributing to around 46% of all ALF cases. It is known that compensatory liver regeneration is stimulated after APAP-induced liver injury and is essential to promote recovery. Bile acids play an important role in liver homeostasis and have protective effect against cell stress and injury at physiological concentration, but are known to be toxic at higher concentrations. Bile acids have also been implicated in stimulation of liver regeneration.
The current study was designed to explore the role of bile acids in initiation of liver injury and stimulation of liver regeneration after APAP overdose in mice. Our data indicate that reduction of bile acids using a resin, cholestyramine (CSA), substantially increased APAP-induced liver injury and delayed liver regeneration. In contrast, supplementation of cholic acid in diet improved liver regeneration. Interestingly, effects of bile acids modulation were not mediated through altered APAP metabolic activation. However, increased JNK activation, a critical step in initiation of APAP toxicity, was implicated in exacerbation of APAP toxicity after CSA treatment. CSA is commonly used in clinical practice for hypercholesterolemia. Thus, our data has great clinical significance suggesting possible drug-drug interaction between APAP and CSA, and caution should be taken in administering APAP for patients taking CSA. Our data also indicate that bile acids have a cytoprotective and pro-regenerative role in APAP induced liver injury which can be potentially exploited for developing therapeutic strategies for APAP-induced ALF.