Water handling and aquaporins in bile formation: recent advances and research trends

Bile is formed by an osmotic process generated by ATPdependent secretion of biliary constituents from the sinusoidal blood or the cellular interior into the bile canalicular lumen. Luminal accumulation of osmotically active solutes, in turn, induces the passive movement of water into the bile canaliculus [1,2]. Canalicular bile (primary bile) is then modified by the bile duct epithelium via secretory and absorptive processes, stored and concentrated in the gallbladder (with few exceptions), and released into the gut. In recent years, there has been considerable progress in understanding the molecular mechanisms underlying bile flow and many of the related solute transporters have been cloned and functionally characterized [3]. However, although the bulk of water generated at the lumen of the biliary tree is a major determinant of bile flow [4], relatively little attention has been given to the molecular mechanisms by which water is transported from the blood to the bile canaliculus or the bile duct. Moreover, studies aimed at answering the long-standing question on the route taken by the water transported across hepatocytes during primary bile formation have been limited and largely indirect. A paracellular pathway between adjacent cells was first evoked [5,6]. Then, a transcellular route across the lipid bilayer or through discrete membrane proteins was favored [7,8]. Knowledge of the phenomenon of water transport in bile formation and bile flow was boosted considerably following the recent recognition of multiple members of the aquaporin family of water channels (AQPs, aquaporins) variously expressed in liver epithelial barriers (for review see Ref. [1]). Recent works as described below indicate roles for aquaporins in liver physiology including bile elaboration and hepatic metabolism as well as in hepatic disorders with altered fluid homeostasis. In this review, we summarize and evaluate the current concepts on the nature of hepatic water transport and present some information on what is known about aquaporins and their functional relevance in liver fluid balance and metabolism. Additionally, we discuss the emerging concepts about the significance of aquaporins in some clinical conditions of the hepatobiliary tract. Crucial areas for future basic and clinical research are also highlighted.