Autophagy induced by exogenous bile acids is therapeutic in a model of α-1-AT deficiency liver disease.
The bile acid nor-ursodeoxycholic acid (norUDCA) has many biological actions, including antiapoptotic effects. Homozygous PIZZ α-1-antitrypsin (A1AT)-deficient humans are known to be at risk for liver disease, cirrhosis, and liver cancer as a result of the accumulation of the toxic, A1AT mutant Z protein within hepatocytes. This accumulation triggers cell death in the hepatocytes with the largest mutant Z-protein burdens, followed by compensatory proliferation. Proteolysis pathways within the hepatocyte, including autophagy, act to reduce the intracellular burden of A1AT Z protein. We hypothesized that norUDCA would reduce liver cell death and injury in A1AT deficiency. We treated groups of PiZ transgenic mice and wild-type mice with norUDCA or vehicle, orally, and examined the effects on the liver. The PiZ mouse is the best model of A1AT liver injury and recapitulates many features of the human liver disease. Mice treated with norUDCA demonstrated reduced hepatocellular death by compensatory hepatocellular proliferation as determined by bromodeoxyuridine incorporation (3.8% control, 0.88% treated, P < 0.04). Ki-67 staining as a marker for hepatocellular senescence and death was also reduced (P < 0.02). Reduced apoptotic signaling was associated with norUDCA, including reduced cleavage of caspases-3, -7, and -8 (all P < 0.05). We determined that norUDCA was associated with a >70% reduction in intrahepatic mutant Z protein (P < 0.01). A 32% increase in hepatic autophagy associated with norUDCA was the likely mechanism. norUDCA administration is associated with increased autophagy, reduced A1AT protein accumulation, and reduced liver injury in a model of A1AT deficiency.
Pediatrics and Biochemistry, Saint Louis University, and Cardinal Glennon Children's Medical Center, St. Louis, Missouri;
Youcai
Y
Tang
Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; and.
Peter
P
Fickert
Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
Michael
M
Trauner
Pediatrics and Biochemistry, Saint Louis University, and Cardinal Glennon Children's Medical Center, St. Louis, Missouri;
Nancy
N
Marcus
Pediatrics and Biochemistry, Saint Louis University, and Cardinal Glennon Children's Medical Center, St. Louis, Missouri;
Keith
K
Blomenkamp
Pediatrics and Biochemistry, Saint Louis University, and Cardinal Glennon Children's Medical Center, St. Louis, Missouri; teckmanj@slu.edu.
Jeffrey
J
Teckman
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D003840:Deoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D014162:Transfection; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; C081331:24-norursodeoxycholic acid
liver; protein conformation; proteolysis; α-1-antitrypsin