Lamprey species appeared over 500 million years and are therefore important evolutionary models for research interests ranging from neuronal signaling, genetics, to organ development. Among this group of jawless vertebrates, the sea lamprey is the largest and most widely distributed. It experiences a drastic life history, which includes a complete metamorphosis. During sea lamprey metamorphosis, the biliary tree and the gallbladder degenerate, in a process referred as biliary atresia. Atresia of the biliary system occurs as a rare disease in human while it is a programmed developmental event in the sea lamprey. The sea lamprey can be used as a model to study the etiology and the adaptive mechanisms of biliary atresia, and the compensatory and adaptive mechanisms in cholestasis based on its various life events including biliary atresia. In this dissertation, I hypothesized that the sea lamprey had evolved unique mechanisms in both liver and intestine in adaption to biliary atresia. To test this hypothesis, I examined sea lamprey liver throughout metamorphic stages at the levels of morphology, histology, mRNA transcripts, and bile salt composition. My results indicate that the sea lamprey has evolved several possible adaptive mechanisms in coping with its developmental biliary atresia. As expected, the enterohepatic circulation is conserved in this basal vertebrate before its metamorphosis. However, the intestine synthesizes and secretes bile salts during and after metamorphosis, or biliary atresia. It is further elucidated that the metamorphic sea lamprey reversed enterohepatic circulation by in vivo perfusion and ex vivo intestine transport assays. It may be an adaptation to the lack of biliary system. Another adaptive mechanism in coping with the aductular life appeared to be dramatic changes in bile salt composition. Also, the down-regulation of cyp7a1, which encodes the rate limiting enzyme of bile acid synthesis, in liver during lamprey biliary atresia resembles the compensatory mechanism in many cholestatic animal models. All of the findings show that the sea lamprey has evolved to cope with biliary atresia and cholestasis. Understanding these mechanisms can shed light on developing treatment and management for patients suffering from biliary atresia and cholestasis.
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