Cholesterol 7alpha-hydroxylase (CYP7A): patterns of messenger RNA expression during rat liver development.

Cholesterol 7-hydroxylase is a rate-limiting enzyme in bile acid synthesis, a major pathway for cholesterol catabolism. It plays a crucial role in postnatal development and survival. In an adult liver, its activity and messenger RNA (mRNA) are heterogeneously distributed with concentration in the pericentral area. We defined how the pattern of cholesterol 7-hydroxylase mRNA evolves during rat liver development, correlated this with its total liver mRNA levels, and determined when its heterogeneous pattern of expression is established. Cholesterol 7-hydroxylase mRNA was undetectable in 18-day-old fetal livers by Northern blot. It was increased markedly in newborns with a homogeneous liver lobular distribution as determined by in situ hybridization. At postnatal day four, mRNA levels were markedly decreased with concomitant appearance of a lobular gradient: mRNA was detected only in a few hepatocytes located around efferent venules. At 22 days, the time of highest mRNA expression, a marked extension of the gradient towards the periportal area was observed, indicating that the increase in total liver cholesterol 7-hydroxylase mRNA level was a result of recruitment of hepatocytes upstream from the central vein area. By 28 days, the adult pattern was observed. Thus, expression of cholesterol 7-hydroxylase mRNA is tightly regulated during rat liver development, both temporally and spatially supporting its critical role in normal postnatal development.

[The role of the liver in the intestinal immune system. Origin of specific B-lymphocytes in the liver following intestinal immunization]. / Untersuchungen zur Rolle der Leber im intestinalen Immunsystem. Herkunft der spezifischen B-Lymphozyten in der Leber nach intestinaler Immunisierung.

After intestinal priming with cholera toxin (CT) the highest number of specific B-cells is found in the liver, whereas after an intestinal booster dose of CT, high numbers of specific B-cells also locate to the intestine. Correspondingly, after priming, 70% of biliary IgA anti-CT are synthesized within the liver and after boosting approximately 30%. To test the hypothesis that the B-cells in the liver are derived from intestinal lymphoid tissue, thoracic duct lymphocytes (TDL) from intestinally primed and boosted donor rats were transferred to syngeneic recipients. TDL from primed donors predominantly homed to the liver of recipients, and TDL from boosted donors in high numbers to the intestine also. High biliary IgA anti-CT titers in both groups of recipients proved that the immune response was transmitted successfully. In the rat, at any rate, the liver is part of the intestinal immune system not only in terms of IgA transport but also as a specific homing organ for intestinal B-cells.

Receptor-mediated uptake of asialoglycoprotein by the primate liver initiates both lysosomal and transcellular pathways.

The degradation of asialoglycoproteins in hepatocytes has been well described in several animal models, but no direct evidence has yet been obtained for asialoglycoprotein processing in the primate liver. A double radiolabeling strategy was employed in the experiments described in this paper to evaluate the fate of asialoorosomucoid in the squirrel monkey. Intravenously injected asialoorosomucoid was taken up by the liver with a half-time of 1 min. Electron microscopic autoradiography showed progression of asialoorosomucoid from the hepatocyte plasma membrane through vesicles to multivesicular bodies and then to secondary lysosomes near the Golgi-rich area of the cell. Over 75% of the grains initially associated with clear endocytic compartments after injection had moved to these later organelles within 20 min. Following degradation of asialoorosomucoid labeled with the Bolton and Hunter reagent, radiocatabolites were secreted into bile, peaking approximately 47 min after injection. We also found that 7 to 8% of the injected protein entered an alternative pathway which led to resecretion of the ligand at the bile canaliculus. This was considerably more than in rats (1 to 3%), but roughly comparable to the amount in guinea pigs (10 to 17%). Intact asialoorosomucoid peaked in monkey bile approximately 27 min after injection and was 3 to 4 times more concentrated than the initial plasma concentration, indicating receptor-mediated transport. Gel filtration chromatography and polyacrylamide gel analysis of the secreted protein indicated that it had arrived in bile unaltered. Since less than 1% of the autoradiographic grains were localized to nonparenchymal cells, the hepatocyte was identified as the cell type simultaneously responsible for both pathways. We propose that missorting of some of the asialoglycoprotein to bile reflects diffusion within intracellular sorting compartments to areas primarily dedicated to the processing of unrelated ligands, such as those newly synthesized for biliary secretion.