Roles of Ileal ASBT and OSTα-OSTβ in Regulating Bile Acid Signaling

Background: In addition to their classical role as detergents, bile acids function as signaling molecules to regulate gastrointestinal physiology, carbohydrate and lipid metabolism, and energy expenditure. The pharmacodynamic potential of bile acids is dependent in part on the tight pharmacokinetic control of their concentration and metabolism, properties governed by their hepatic synthesis, enterohepatic cycling, and biotransformation via host and gut microbiota-catalyzed pathways. Key Messages: By altering the normal cycling and compartmentalization of bile acids, changes in hepatobiliary or intestinal transport can affect signaling and lead to the retention of cytotoxic hydrophobic bile acids and cell injury. This review discusses advances in our understanding of the intestinal transporters that maintain the enterohepatic cycling of bile acids, signaling via bile acid-activated nuclear and G protein receptors, and mechanisms of bile acid-induced cell injury. Conclusions: Dysregulated expression of the Asbt and Ostα-Ostβ alters bile acid signaling via the gut-liver farnesoid X receptor-fibroblast growth factor 15/19 axis and may contribute to other bile acid-regulated metabolic and cell injury pathways.

The role of immunoglobulin A in prolonged and relapsing hepatitis A virus infections

Hepatitis A virus (HAV) infections result in different courses of the disease, varying between normal, prolonged and relapsing. However, the reason for these heterogeneous clinical appearances is not understood. As HAV–anti-HAV IgA immunocomplexes (HAV–IgA) infect hepatocytes, IgA was postulated as a carrier supporting hepatotropic transport of HAV, and it was speculated that this carrier mechanism contributes to the various clinical outcomes. In this study, the IgA-carrier mechanism was investigated in a mouse model. We show that HAV–IgA immunocomplexes efficiently reached the liver not only in HAV-seronegative mice, but also, and this is in contrast to free-HAV particles, in immunized HAV-seropositive animals. This IgA-mediated transport of HAV to the liver in the presence of immunity depended on the stage of development of the immune response. We conclude that over a period of several weeks after infection, anti-HAV IgA is able to promote an enterohepatic cycling of HAV, resulting in continuous endogenous reinfections of the liver. Our experiments indicate that highly avid IgG antibodies, which are present at later times of the infection, can terminate the reinfections. However, the endogenous reinfections in the presence of a developing neutralizing immunity might contribute to prolonged as well as to relapsing courses of HAV infections. Furthermore, the results show that serum IgA may act as an infection protracting factor.