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J Biol Chem, Vol. 274, Issue 4, 2157-2165, January 22, 1999
From the Mechanisms directing position-specific liver gene
regulation are incompletely understood. To establish whether this
aspect of hepatic gene expression is an inveterate phenomenon, we used transplanted hepatocytes as reporters in dipeptidyl peptidase IV-deficient F344 rats. After integration in liver parenchyma, the
position of transplanted cells was shifted from periportal to
perivenous areas by targeted hepatic ablations with carbon tetrachloride. In controls, transplanted cells showed greater glucose-6-phosphatase and lesser glycogen content in periportal areas.
This pattern was reversed when transplanted cells shifted from
periportal to perivenous areas. Transplanted hepatocytes in perivenous
areas exhibited inducible cytochrome P450 activity, which was deficient
in periportal hepatocytes. Moreover, cytochrome P450 activity was
rapidly extinguished in activated hepatocytes when these cells were
transplanted into the nonpermissive liver of suckling rat pups. In
cells isolated from the normal F344 rat liver, cytochrome P450
inducibility was originally greater in perivenous hepatocytes; however,
periportal cells rapidly acquired this facility in culture conditions.
These findings indicate that the liver microenvironment exerts
supremacy over prior differentiation state of cells in directing
position-specific gene expression. Therefore, persistence of
specialized hepatocellular function will require interactions with
regulatory signals and substrate availability, which bears upon further
analysis of liver gene regulation, including in progenitor and/or stem cells.
Position-specific Gene Expression in the Liver Lobule Is
Directed by the Microenvironment and Not by the Previous Cell
Differentiation State
§¶,
¶,
¶,
¶,
¶, and
**
Marion Bessin Liver Research Center and
§ Cancer Research Center, Departments of ¶ Medicine and
** Radiation Oncology, Albert Einstein College of Medicine,
Bronx, New York 10461
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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