The role of bile acids during cholestasis in mice and man

Abstract

Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Cholestasis leads to significant liver toxicity, biliary hyperplasia, and liver cirrhosis. The molecular mechanisms behind the early liver injury associated with cholestasis are extensively studied, but the details, especially in man, are not well understood. The predominant hypothesis for the cause of cholestatic liver injury is that a buildup of toxic bile acids in liver and serum leads to hepatocellular apoptosis. While the direct toxicity of bile acids is supported by in vitro studies in primary rat hepatocytes and transfected human hepatoma lines, recent studies measuring the concentrations of individual bile acids after cholestasis in vivo has led us to reevaluate mechanisms of cytotoxicity during cholestasis, as bile acid levels in man may not reach the necessary concentration for onset of toxicity. Thus, the overarching goal of this dissertation project was to determine the effect of pathophysiologically relevant concentrations of bile acids in man, with an emphasis on the human condition. This project is focused upon understanding the mechanisms and cellular events that determine how cholestasis results in liver injury with the hope of furthering understanding the progression of the injury in vivo both in human patients, human hepatocyte lines and murine models. This study resulted in a number of findings that are potentially significant to the field of cholestatic liver injury. Primarily, human hepatocytes are resistant to bile acid induced apoptosis, and moreover human patients undergo relatively little apoptosis during cholestatic liver injury. This is likely due to a combination of dramatic differences between human and rodent bile acid compositions and the pathophysiology of in vivo models versus in vitro modeling in rodents. Further work is necessary to fully ascertain how, and why, human hepatocytes and human patients undergo liver injury during cholestasis.