Signal transduction and hepatocellular bile acid transport: Cross talk between bile acids and second messengers
Section snippets
Hepatobiliary bile acid transport
Alteration of the hepatic transport of bile acids can result in their accumulation in the liver and potential spillover of bile acids from the liver to the systemic circulation. The accumulation in the liver of potentially toxic and detergent bile acids will lead to cellular damage and liver dysfunction. It is therefore critical that hepatocellular transport of bile acids be tightly regulated.
Hepatocellular calcium homeostasis
Calcium plays a critical role in the regulation of cellular functions. Rapid changes in the cytosolic free (ionized) calcium level result in decreased DNA and protein synthesis as well as stimulated glycogen breakdown. In most cells, including hepatocytes, different mechanisms intervene to control the intracellular cytosolic calcium concentration. In the hepatocyte, the ionized cytosolic calcium concentration is ̃100 nmol/L, whereas the total serum and biliary calcium concentrations are ̃2.5
cAMP synthesis
Hormones such as glucagon119 and vasoactive intestinal peptide120 as well as β-adrenergic agonists121 promote hepatocellular cAMP synthesis from ATP through the activation of adenylyl cyclase and mediated by a stimulatory GTP-binding protein (Gs; see Figure 1 for details). For decades, cAMP has been proposed to be one of the principal second messengers involved in the maintenance of cellular function and responsiveness to external stimuli. Through cAMP synthesis and cAMP-dependent protein
Bile acids and calcium homeostasis
Bile acids were first suggested to act as calcium ionophores and to induce calcium influx in various cells, including erythrocytes,170 kidney cells,171 enterocytes,172 and hepatocytes. 173, 174 A considerable amount of data show that different bile acids differentially affect hepatocellular calcium homeostasis112, 173, 180, 174, 175, 176, 177, 178, 179 (Table 1 and Figure 3).
Conclusion and future directions for research
It is apparent that bile acid transport may have several sites of regulation. Because there are discrete sites for hepatocellular bile acid uptake, synthesis, intracellular transport, and excretion that involve an array of biochemical components, multiple mechanisms may play a role in the cellular regulation of bile secretion by second messengers (Figure 2). On the other hand, it is becoming clearer that bile acids at both physiological and therapeutic concentrations can regulate different
Acknowledgements
The authors thank Dr. Susan Ceryak, Department of Medicine, George Washington University Medical Center, for her valuable and thoughtful discussions during the preparation and editing of the manuscript.
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