Development of enzymic zonation in liver parenchyma is related to development of acinar architecture

Lamers, Wouter H.; Janzen, J. W. Gaasbeek; Kortschot, A. te; Charles, R.; Moorman, Antoon F.M.

doi:10.1111/j.1432-0436.1987.tb00173.x

Cited by 51 publications

(42 citation statements)

References 27 publications

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“…Although the arterial blood supply is the same for both liver and pancreatic hepatocytes, the major difference is that the hepatocytes in the liver acinus are subjected to metabolic and hormonal gradients from portal blood but pancreatic hepatocytes are not. We favor this view, because it is consistent with the observation that the stable repression of the GS gene during ontogeny in most hepatocytes except for those in the pericentral location occurs after the development of acinar structure (15), which underscores the postnatal alterations in the blood composition due to establishment of functional portal system. It is conceivable that GS expression in liver is suppressed by some factor present in the portal venous supply and this suppression is overcome by interaction of the hepatocytes with specialized matrix at the terminal venule and that this interaction also results in the suppression of CPS-I only in these cells.…”

Section: Discussionsupporting

confidence: 81%

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Coexpression of glutamine synthetase and carbamoylphosphate synthase I genes in pancreatic hepatocytes of rat.

Yeldandi

Tan

Dwivedi

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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In the mammalian liver the distribution of ammonia-detoxifying enzymes, glutamine synthetase (GS) and carbamoylphosphate synthase I (ammonia) (CPS-I), is mutually exclusive in that these enzymes are expressed in two distinct populations of hepatocytes that are zonally demarcated in the liver acinus. In the present study we examined the distribution of GS and CPS-I in pancreatic hepatocytes to ascertain if the expression of these two genes in these hepatocytes is also mutually exclusive. Multiple foci of hepatocytes showing no clear acinar organization develop in the adult rat pancreas as a result of a change in the differentiation commitment after dietary copper deficiency. Unlike liver, GS and CPS-I are detected by immunofluorescence in all pancreatic hepatocytes. In situ hybridization revealed that all pancreatic hepatocytes contain GS and CPS-I mRNAs. The sizes of these two mRNAs in pancreas with hepatocytes are similar to those of the liver. The concomitant expression of GS and CPS-I genes in pancreatic hepatocytes may be attributed, in part, to the absence of portal blood supply to the pancreas vis-a-vis the lack of hormonal/metabolic gradients as well as to possible matrix homogeneity in the pancreas.Hepatocyte differentiation is characterized by the acquisition of the typical phenotypic features and expression of liverspecific proteins (1). Although many of these specific proteins are expressed equally by all the hepatocytes in the liver acinus, certain enzymes are heterogeneous in their distribution (1, 2). For example, the periportal region contains higher concentrations of enzymes active in gluconeogenesis, whereas the pericentral area is enriched in detoxification enzymes (1). The striking complementary distribution of ammonia-metabolizing enzymes glutamine synthetase (GS; EC 6.3.1.2) and carbamoylphosphate synthase I (CPS-I; EC 6.3.4.16) in the adult rat and mouse liver further exemplifies this heterogeneity (3-6). CPS-I is homogeneously distributed in all liver cells except for a single layer of hepatocytes surrounding the central veins (3). On the other hand, GS is localized exclusively to a narrow zone of pericentral hepatocytes that does not express CPS-I (4-6). The mutually exclusive expression of either GS or CPS-I has been shown to be unique to the liver of mammals among all vertebrates (5). The enzyme heterogeneity in the liver has been attributed largely to gradients of metabolites and regulatory factors that exist along the liver acinus (1). It has been suggested (6) that functional heterogeneity in the adult mammalian liver, especially with regard to GS expression, is due to the positional regulation of gene expression. This implies that gene expression in hepatocytes at various positions in the acinus depends upon the possible differences in the composition of extracellular matrix (6).The present study was undertaken to ascertain whether the mutually exclusive expression of either CPS-I or GS observed in the mammalian liver, also manifests in the hepatocytes that differentiate in ...

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Section: Discussionsupporting

confidence: 81%

“…Immunohistochemical Localization of CPS-I and GS. The immunohistochemical localization pattern ofCPS-I and GS in the adult rat liver is similar to that reported by others (1, [3][4][5]15). CPS-I is observed in all hepatocytes in the liver lobule with the exception of a narrow zone of cells lining the central vein (data not illustrated).…”

supporting

confidence: 89%

Coexpression of glutamine synthetase and carbamoylphosphate synthase I genes in pancreatic hepatocytes of rat.

Yeldandi

Tan

Dwivedi

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…: 31-20-5664927; Fax: 31-20-6976177. 1 The abbreviations used are: CPS, carbamoyl-phosphate synthetase I; kbp, kilobase pair(s); nt, nucleotides; FCS, fetal calf serum; UTR, untranslated region; TK, thymidine kinase; Bt 2 cAMP, dibutyryl-cyclic AMP; IBMX, 3-isobutyl-1-methylxanthine; (u)ORF, (upstream) open reading frame; CRE, cyclic AMP-responsive element; GRE, glucocorticoid-responsive element; bp, base pair(s); RSV, Rous sarcoma virus; CREB, cAMP response element-binding protein; RT-PCR, reverse transcriptase-polymerase chain reaction.…”

Section: Methodsmentioning

confidence: 99%

The Far-upstream Enhancer of the Carbamoyl-phosphate Synthetase I Gene Is Responsible for the Tissue Specificity and Hormone Inducibility of Its Expression

Christoffels

Hoff

Moorman

et al. 1995

Journal of Biological Chemistry

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The role of the proximal promoter and the far-upstream enhancer in the hepatocyte-specific and hormonal regulation of the carbamoyl-phosphate synthetase I (CPS) gene was investigated in transient transfection assays using primary rat hepatocytes, hepatoma cells, and fibroblasts. These experiments revealed that the activity of the promoter is comparable in all cells tested and is, therefore, not responsible for tissue-specific expression. The 5-untranslated region of the mRNA is a major, non-tissue specific stimulator of expression in FTO-2B hepatoma cells, acting at the post-transcriptional level. A 469-base pair DNA fragment, 6 kilobase pairs upstream of the transcription start-site in the CPS gene, confers strong hormone-dependent tissue specific expression, both in combination with the CPS promoter and a minimized viral thymidine kinase promoter. Sequences similar to a cyclic AMP-responsive element and a glucocorticosteroid-responsive element were found in the isolated enhancer. Substitutional mutations in these sites strongly affected hormone-induced expression. Analysis of the interaction between the enhancer and parts of the CPS promoter revealed that, in addition to the TATA box, the GAG box, a motif similar to the GC box near the TATA motif, is instrumental in conferring the enhancer activity.

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“…downstream) region of the liver lobule arise from the periportal (i.e. upstream) hepatocytes [17][18][19][20], but other extracellular signals have been proposed to be involved in the regulation of the position-specific expression of GS in the liver, including hormones [21], the position of the hepatocyte on the portocentral axis [22], cell-cell interactions [23][24][25], the innervation pattern [26] and cell lineage [27]. Furthermore, glucocorticoids have often been shown to enhance the levels of GS gene expression in a variety of organs, such as the central nervous system, kidney, muscle, lung, intestine (see for example [28][29][30][31][32][33][34][35][36][37][38][39]), and possibly Abbreviations used : GS, glutamine synthetase ; CAT, chloramphenicol acetyltransferase ; BAT, brown adipose tissue.…”

Section: Introductionmentioning

confidence: 99%

Role of the 5′ enhancer of the glutamine synthetase gene in its organ-specific expression

Lie-Venema

Boer

Moorman

et al. 1997

Biochemical Journal

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In mammals, glutamine synthetase (GS) is expressed in a large number of organs, but the precise regulation of its expression is still obscure. Therefore a detailed analysis of the activity of the upstream regulatory element of the GS gene in the transcriptional regulation of its expression was carried out in transgenic mice carrying the chloramphenicol acetyltransferase (CAT) gene under the control of the upstream regulatory region of the GS gene. CAT and GS mRNA expression were compared in liver, epididymis, lung, adipocytes, testis, kidney, skeletal muscle and gastrointestinal tract, both quantitatively by ribonuclease-protection analysis and topographically by in situ hybridization. It was found that the upstream regulatory region is active with respect both to the level and to the topography of GS gene expression in liver, epididymis, gastrointestinal tract (stomach, small intestine and colon) and skeletal muscle. On the other hand, in the kidney, brain, adipocytes, spleen, lung and testis, GS gene expression is not or only partly regulated by the 5´ enhancer. A second enhancer, identified within the first intron, may regulate GS expression in the latter organs. Furthermore, CAT expression in the brain did not co-localize with that of GS, showing that the 5´ regulatory region of the GS gene does not direct its expression to the astrocytes.

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Development of enzymic zonation in liver parenchyma is related to development of acinar architecture

Cited by 51 publications

References 27 publications

Coexpression of glutamine synthetase and carbamoylphosphate synthase I genes in pancreatic hepatocytes of rat.

Coexpression of glutamine synthetase and carbamoylphosphate synthase I genes in pancreatic hepatocytes of rat.

The Far-upstream Enhancer of the Carbamoyl-phosphate Synthetase I Gene Is Responsible for the Tissue Specificity and Hormone Inducibility of Its Expression

Role of the 5′ enhancer of the glutamine synthetase gene in its organ-specific expression

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