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.
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Michal
M
Pyzik
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Timo
T
Rath
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Timothy T
TT
Kuo
Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Sanda
S
Win
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Kristi
K
Baker
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.|Division of Gastroenterology and Nutrition, Children's Hospital Boston, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
Jonathan J
JJ
Hubbard
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Rosa
R
Grenha
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Amit
A
Gandhi
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Thomas D
TD
Krämer
Biogen Idec-Hemophilia, Inc., Waltham, MA 02451.
Adam R
AR
Mezo
Biogen Idec-Hemophilia, Inc., Waltham, MA 02451.
Zachary S
0000-0002-3481-2571
ZS
Taylor
Biogen Idec-Hemophilia, Inc., Waltham, MA 02451.
Kevin
K
McDonnell
Zenobia Therapeutics, Inc., San Diego, CA 92121.
Vicki
V
Nienaber
Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo 0424, Norway.|Department of Biosciences, University of Oslo, Oslo 0316, Norway.
Jan Terje
JT
Andersen
Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114.|Molecular Pathology Unit, Massachusetts General Hospital, Charlestown 02129 MA.|Department of Pathology, Harvard Medical School, Boston 02115 MA.
Atsushi
A
Mizoguchi
Syntimmune Inc., New York, NY 10010.
Laurence
L
Blumberg
Syntimmune Inc., New York, NY 10010.
Shalaka
S
Purohit
Syntimmune Inc., New York, NY 10010.
Susan D
SD
Jones
The Jackson Laboratory, Bar Harbor, ME 04609.
Greg
G
Christianson
Division of Gastroenterology and Nutrition, Children's Hospital Boston, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
Wayne I
WI
Lencer
Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo 0424, Norway.|Department of Biosciences, University of Oslo, Oslo 0316, Norway.
Inger
I
Sandlie
Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Neil
N
Kaplowitz
The Jackson Laboratory, Bar Harbor, ME 04609.
Derry C
DC
Roopenian
Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; rblumberg@bwh.harvard.edu.
Richard S
RS
Blumberg
D000082:Acetaminophen / Q000009:adverse effects / Q000378:metabolism; D000418:Albumins / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D000075462:Serum Albumin, Human / Q000235:genetics / Q000378:metabolism; D057900:Transcytosis / Q000235:genetics
D000418:Albumins; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D000082:Acetaminophen; C100688:Fc receptor, neonatal; D000075462:Serum Albumin, Human
FcRn; albumin; bile; liver; toxin