Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.

The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.

Microsatellite genetic structure and cytonuclear discordance in naturally fragmented populations of deer mice (Peromyscus maniculatus).

The Great Lakes impose high levels of natural fragmentation on local populations of terrestrial animals in a way rarely found within continental ecosystems. Although separated by major water barriers, woodland deer mouse (Peromyscus maniculatus gracilis) populations on the islands and on the Upper Peninsula (UP) and Lower Peninsula (LP) of Michigan have previously been shown to have a mitochondrial DNA contact zone that is incongruent with the regional landscape. We analyzed 11 microsatellite loci for 16 populations of P. m. gracilis distributed across 2 peninsulas and 6 islands in northern Michigan to address the relative importance of geographical structure and inferred postglacial colonization patterns in determining the nuclear genetic structure of this species. Results showed relatively high levels of genetic structure for this species and a significant correlation between interpopulation differentiation and separation by water but little genetic structure and no isolation-by-distance within each of the 2 peninsulas. Genetic diversity was generally high on both peninsulas but lower and correlated to island size in the Beaver Island Archipelago. These results are consistent with the genetic and demographic isolation of Lower Peninsula populations, which is a matter of concern given the dramatic decline in P. m. gracilis abundance on the Lower Peninsula in recent years.