Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse.
OBJECTIVE
To examine the in vivo phenotype associated with hepatic metastatic lymph node 64 (MLN64) over-expression.


METHODS
Recombinant-adenovirus-mediated MLN64 gene transfer was used to overexpress MLN64 in the livers of C57BL/6 mice. We measured the effects of MLN64 overexpression on hepatic cholesterol content, bile flow, biliary lipid secretion and apoptosis markers. For in vitro studies cultured CHO cells with transient MLN64 overexpression were utilized and apoptosis by TUNEL assay was measured.


RESULTS
Livers from Ad.MLN64-infected mice exhibited early onset of liver damage and apoptosis. This response correlated with increases in liver cholesterol content and biliary bile acid concentration, and impaired bile flow. We investigated whether liver MLN64 expression could be modulated in a murine model of hepatic injury. We found increased hepatic MLN64 mRNA and protein levels in mice with chenodeoxycholic acid-induced liver damage. In addition, cultured CHO cells with transient MLN64 overexpression showed increased apoptosis.


CONCLUSIONS
In summary, hepatic MLN64 over-expression induced damage and apoptosis in murine livers and altered cholesterol metabolism. Further studies are required to elucidate the relevance of these findings under physiologic and disease conditions.
Tichauer
Juan-Enrique
JE
Departamento de Gastroenterologia, Pontificia Universidad Catolica de Chile, Marcoleta 367, Santiago, Chile.
Morales
Maria-Gabriela
MG
Amigo
Ludwig
L
Galdames
Leopoldo
L
Klein
Andres
A
Quinones
Veronica
V
Ferrada
Carla
C
Alvarez
Alejandra-R
AR
Rio
Marie-Christine
MC
Miquel
Juan-Francisco
JF
Rigotti
Attilio
A
Zanlungo
Silvana
S
D000256:Adenoviridae / Q000235:genetics; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D002635:Chenodeoxycholic Acid; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C486529:MLN64 protein, mouse; D010750:Phosphoproteins; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D000469:Alkaline Phosphatase