CELL DIFFERENTIATION WITHIN THE LIVER ACINUS

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One of the most compelling reasons to propose that cell differentiation has occurred within the hepatic acinus is the induction of LM2, a specific form of liver microsomal cytochrome P-450, by phenobarbital. This induction occurs predominantly in one population of hepatocytes, those of acinar zone 3. The specific aims of this proposal are to determine: a) the capability of specific hepatocytes to respond to the phenobarbital induction of LM2 in fetal and newborn liver, b) the role of the microenvironment (specifically of oxygen, hormonal and substrate concentrations in blood bathing hepatocytes) in modulating the appearance of this differentiated capability, and c) whether the capability of certain hepatocytes to respond to the phenobarbital induction of LM2 appears prior to or after the assembly of the liver into acinar zones. The fetal liver has been chosen as the main experimental model, since in the fetus the liver is comprised of two distinct functional units subject to very different environmental conditions. The initial experimental approach will be to induce LM2 in adult guinea pig liver by the administration of phenobarbital, to isolate LM2 and to raise antibodies in rabbits against the purified form of this protein. Subsequently, the induction of LM2 in newborn and fetal guinea pig livers will be assessed qualitatively and quantitatively by immunofluorescence and immunocytochemistry using the specific antibody generated against guinea pig LM2. This proposal represents an initial approach to elucidate some of the mechanisms which regulate the imprinting of this specific differentiated capability (LM2 induction) by phenobarbital in certain hepatocytes of the developing liver. This data is to be used in pursuing the long objective of this group, the elucidation of the molecular mechanisms and regulation involved in the expression of these genetic capabilities in selective hepatocytes.