Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity

Acetaminophen (APAP) overdose is a leading cause of acute liver failure with a limited therapeutic option. It is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Using our imaging toolbox, we investigated the role of BAs in APAP-induced liver injury and identified a therapeutic intervention. In a mouse model, we observed that APAP compromises the blood-bile barrier so that BAs from the bile canaliculi leak into the paracellular space and sinusoidal blood from where they are taken up into hepatocytes, secreted into bile canaliculi and again leak into the sinusoidal blood leading to a process we named ‘futile bile acid cycling’. Consequently, BA concentrations in hepatocytes amount to cytotoxic levels which aggravates APAP-induced liver injury. Interestingly, interruption of BA uptake by hepatocytes - by blocking of the uptake transporters - after APAP overdose strongly ameliorates hepatotoxicity.

Inhibition of the renal ASBT prevents cholemic nephropathy

Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases, and no specific treatment is available. To investigate the mechanism and identify therapeutic interventions, we studied the liver-kidney axis in cholestasis using our intravital imaging toolbox. In the acute phase after bile duct ligation (BDL) in mice, bile infarcts are formed by rupture of the apical hepatocyte membrane, and cause shunting of bile to the sinusoidal blood. In the chronic phase after BDL, several adaptive mechanisms are established that limit BA load in hepatocytes but further increase it in the systemic blood.

Flooding of the systemic circulation with bile acids in cholestasis coincides with the development of CN; however, the driving mechanism of CN was not clear. Using our imaging tools, we show that BA are reabsorbed from the renal tubular lumen into proximal renal tubular epithelial cells (TEC) and that BA enrichment in TEC is followed by oxidative stress and cell death, damage of peritubular capillaries and massive leakage of BA into the renal interstitium, and fibrosis. Based on this mechanism we used a systemically bioavailable inhibitor that blocks the renal apical sodium-dependent bile acid transporter (ASBT); consequently, urinary excretion of BA was massively enhanced, which not only prevented CN but also systemically reduced BA concentrations. Preserved ASBT expression in human TEC was demonstrated in biopsies from CN patients, highlighting the translational potential of treating CN by targeting ASBT.