Chapter 3 - Mechanisms of Bile Formation and the Pathogenesis of Cholestasis

Summary

Bile formation and flow is an essential physiological function. Adequate bile flow is necessary for innumerable daily functions including digestion, metabolism, growth, development, toxin elimination and adaptation to liver disease. Cholestasis, a slowing or, in its extreme form, cessation of bile flow, is a pathophysiological process that interrupts the necessary functions of bile while biliary constituents accumulate intrahepatically [1–3]. This accretion of bile leads to liver damage from the multiple effects of retained biliary constituents, including various lipids, toxins, and as a principal effector – bile acids [4–6]. These effects of cholestasis, regardless of cause, are amplified and accelerated in the infant, rendering the consequences of unaddressed neonatal cholestasis urgent [1, 7–9]. A molecular understanding of the determinants of bile formation is helpful to link these individual solutes to the responsible genes and functions in normal biology and in cholestasis. Bile formation and flow relies upon membrane transporters of biliary solutes, and their regulators, that function to deliver each of the molecular constituents into bile. The focus of this chapter is to lay the groundwork of current knowledge of the mechanisms of bile formation and to explore normal and pathophysiological processes when these mechanisms are impaired. Moreover, very recent work based upon the knowledge of bile formation has led to new therapeutic targeting, with the goal of filling the serious gap in effective anti-cholestatic therapies.