Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2862-E2871. doi: 10.1073/pnas.1618291114.

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.

Pyzik M1, Rath T1, Kuo TT1, Win S2, Baker K1, Hubbard JJ1,3,4, Grenha R1, Gandhi A1, Krämer TD1, Mezo AR5, Taylor ZS5, McDonnell K5, Nienaber V6, Andersen JT7,8, Mizoguchi A9,10,11, Blumberg L12, Purohit S12, Jones SD12, Christianson G13, Lencer WI3,4, Sandlie I7,8, Kaplowitz N2, Roopenian DC13, Blumberg RS14.




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 FcRnalbumin 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.

KEYWORDS:  FcRn; albumin; bile; liver; toxin

PMID: 28330995: DOI: 10.1073/pnas.1618291114