Subcellular and molecular mechanisms of bile secretion.

One of the liver's principal functions is the formation of bile, which is requisite for digestion of fat and elimination of detoxified drugs and metabolites. Bile is a complex fluid made up of water, electrolytes, bile acids, pigments, proteins, lipids, and a multitude of chemical breakdown products. In this review, we have summarized the source of various biliary components, the route by which they end up in bile, including the underlying subcellular and molecular mechanisms, and their contribution to bile formation. One of the reasons why bile formation is so complex is that there are many mechanisms with overlapping substrate specificities, i.e., many biochemically unrelated biliary constituents share common transport mechanisms. Additionally, biliary constituents may reach bile by more than one pathway. Some biliary components are critical for bile formation; others are of minor significance for bile formation but play a major physiological role. The major driving force for bile formation is the uptake and transcellular transport of bile salts by hepatocytes. The energy for bile formation comes from the sodium gradient created by the basolateral Na+/K(+)-ATPase, to which bile salt transport is coupled. The secretory pathway for bile salts involves uptake at the basolateral surface of the hepatocyte, vectorial transcellular movement, and transport across the canalicular membrane into the canalicular lumen. Hydrophilic bile salts are taken up via a sodium-dependent, saturable, carrier-mediated process coupled to the Na+/K(+)-ATPase. This uptake mechanism is also shared by other substrates, such as electroneutral lipids, cyclic oligopeptides, and a wide variety of drugs. Hydrophobic bile acids are taken up by a sodium-independent facilitated carrier-mediated mechanism in common with other organic ions, including sulfated bile acids, sulfobromophthalein, bilirubin, glutathione, and glucuronides, or by nonsaturable passive diffusion. Two major carrier proteins have been identified on the hepatocyte basolateral membrane: a 48-kDa protein that appears to be involved with Na(+)-dependent bile salt uptake, and a 54-kDa protein, thought to be associated with Na(+)-independent bile salt uptake. The intracellular transport of bile salts may involve cytosolic carrier proteins, of which several have been identified. Some evidence suggests a vesicular transport mechanism for bile salts. Since bile acids clearly do not enter the cell by endocytosis, formation of transport vesicles must be a more distal event in the transcellular translocation process. Some bile salts appear to be transported within the same unilamellar vesicles that are involved in the secretion of cholesterol and phospholipid.(ABSTRACT TRUNCATED AT 400 WORDS)