Zonal Gene Expression in Mouse Liver Resembles Expression Patterns of Ha-ras and β-Catenin Mutated Hepatomas

Abstract

ABSTRACT:Hepatocytes of the periportal and perivenous zones of the liver lobule differ in their levels and activities of various enzymes and other proteins. We have recently suggested that ␤-catenin-and Ras-dependent signaling pathways play an important role in the regulation of perivenous and periportal gene expression profiles. This hypothesis was primarily based on similarities in zonal differences in gene expression of hepatocytes from normal liver with gene expression patterns of liver tumors: several proteins and mRNAs preferentially expressed in periportal hepatocytes were often overexpressed in Ha-ras mutated mouse liver tumors, whereas perivenous markers were overexpressed in Ctnnb1 (encoding ␤-catenin) mutated tumors. We have now extended this work by use of data from two previously conducted microarray analyses aimed to analyze 1) global gene expression patterns of Ha-ras and Ctnnb1 mutated mouse liver tumors and 2) transcriptome differences between periportal and perivenous mouse hepatocytes. By comparison of the datasets, 134 genes or expressed sequences were identified that were present in both datasets. Gene expression patterns in perivenous hepatocytes and Ctnnb1 mutated hepatoma cells were strongly correlated: 96.5% of the genes present in both datasets were regulated in the same direction. In analogy, expression of 74.1% of the genes deregulated in Ha-ras mutated tumors was correlated with the respective expression patterns in periportal hepatocytes. These findings favor the hypothesis that gene expression patterns in periportal and perivenous hepatocytes are regulated, at least in part, by Ras-and ␤-catenin-dependent signaling pathways.Based on the location of the blood vessels, the terminal branches of the portal and the hepatic (central) veins, and the direction of the blood flow, the individual liver lobule can be subdivided into an upstream "periportal" and a downstream "perivenous" (pericentral) region. Hepatocytes located in either of the two regions have different, often complementary functions, as indicated by differences in the content and activity of several metabolic key enzymes (for review see Jungermann and Katz, 1989;Gebhardt, 1992). This so-called "zonation" of metabolism in the liver is also of particular impact on the metabolism of pharmaceuticals and xenobiotics, since most of the enzymes involved in the metabolism of such compounds show distinct differences in basal as well as inducible expression between perivenous and periportal hepatocytes, with the main detoxification enzymes of both phase I and phase II of xenobiotic metabolism being located preferentially in perivenous hepatocytes (for reviews on zonation of xenobiotic metabolism see Jungermann and Katz, 1989;Oinonen and Lindros, 1998). As a consequence, various exogenous compounds lead to a preferential damage of hepatocytes located in either the perivenous or periportal area of the liver lobule (for review see Lindros, 1997).We have recently developed a hypothesis to explain the mechanisms that govern zonal differenc...

β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice

“…Therefore, high levels of β-catenin signaling are incompatible with the molecular environment that enables Kras to specify a ductal lineage with the capacity to develop into PDA. Interestingly, this interaction may be similar to the antagonism of β-catenin target genes by Hras signaling that is observed in the zonation of periportal versus pericentral hepatocytes in the liver (39,40), although the mechanism of inhibition in this context is unclear. Understanding how β-catenin levels and signaling are controlled during the initiation of ADM/PanIN, whether Kras directly inhibits β-catenin, and which β-catenin targets must be blocked for Kras to take advantage of an otherwise permissive differentiation state also may provide new insight into the development of PDA precursors as well as an important developmental signaling interaction.…”

Phenotype and growth behavior of residual β-catenin-positive hepatocytes in livers of β-catenin-deficient mice

“…Aberrant mutational activation of b-catenin in mouse liver tumors, as well as transgenic activation of the Wnt pathway, induces a 'perivenous'-like phenotype, irrespective of the cell's position with respect to the hepatic blood vessels (Benhamouche et al 2006;Braeuning and Schwarz 2010;Braeuning et al 2007;Cadoret et al 2002;Giera et al 2010;Hailfinger et al 2006). In contrast, hepatocytespecific knockout of Ctnnb1 (encoding b-catenin) causes a broad-spectrum loss of perivenous gene expression (Braeuning et al 2009;Sekine et al 2006;Tan et al 2006).…”

“…RNA isolation and real-time RT-PCR RNA was isolated and reverse transcribed as recently described (Braeuning et al 2007). Expression analysis was performed on a LightCycler real-time PCR system (Roche, Mannheim, Germany).…”

Inducibility of Drug-Metabolizing Enzymes by Xenobiotics in Mice with Liver-Specific Knockout ofCtnnb1

“…Based on the observation that mouse hepatomas with mutationally activated ␤-catenin express high levels of various "perivenous" marker mRNAs and proteins including several P450 isoenzymes (Loeppen et al, 2005;Stahl et al, 2005;Braeuning et al, 2007a), we postulated that ␤-catenin-dependent signaling determines the perivenous hepatocyte gene expression profile including the main drug-metabolizing enzymes . Accordingly, treatment of cultured hepatocytes with inducers of ␤-catenin signaling was able to induce the expression of Cyp1a1, Cyp2b10, and Cyp2e1 mRNAs .…”