Subcutaneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasis.
Several genetic metabolic liver diseases share the pathological features of combined steatosis and cholestasis, or steatocholestasis. The aims of this study were to develop and characterize an in vivo model for steatocholestasis and to evaluate the effects of an antioxidant treatment on liver injury, oxidative stress, and mitochondrial perturbations in this model. Obese and lean Zucker rats received intravenous (IV) injections of glycochenodeoxycholic acid (GCDC) and were killed 4 hours later. Liver enzymes were measured; the liver histology was assessed, and hepatic mitochondria were analyzed for mitochondrial lipid peroxidation. In separate experiments, rats received daily injections of subcutaneous (SQ) vitamin E before GCDC infusion. Bile acid-induced injury (serum AST and ALT and liver histology) was more severe in the obese rats than in the lean rats, characterized predominantly by extensive cell necrosis with minimal evidence of apoptosis. SQ vitamin E provided significant protection against IV GCDC-induced hepatic injury, in vitro GCDC-induced permeability transition, and cytochrome C and apoptosis-inducing factor release from isolated mitochondria.


CONCLUSIONS
Steatosis sensitizes the liver to bile acid-induced necrotic hepatocyte injury, which is responsive to vitamin E therapy.
Pediatric Liver Center and Liver Transplantation Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Colorado at Denver Health Sciences Center, Denver, CO, USA.
Jason S
JS
Soden
Michael W
MW
Devereaux
Joel E
JE
Haas
Eric
E
Gumpricht
Rolf
R
Dahl
Jane
J
Gralla
Maret G
MG
Traber
Ronald J
RJ
Sokol
D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity; D007279:Injections, Subcutaneous; D008099:Liver / Q000473:pathology; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D014807:Vitamin D / Q000008:administration & dosage*
D014807:Vitamin D; D005999:Glycochenodeoxycholic Acid; D000255:Adenosine Triphosphate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase