Zonal gene expression in murine liver: Lessons from tumors

Abstract

Gene expression in hepatocytes within the liver lobule is differentially regulated along the portal to central axis; however, the mechanisms governing the processes of zonation within the lobule are unknown. A model for zonal heterogeneity in normal liver is proposed, based on observations of differential expression of genes in liver tumors from mice that harbor activating mutations in either Catnb (which codes for ␤-catenin) or Ha-ras. According to the model, the regulatory control consists of two opposing signals, one delivered by endothelial cells of the central veins activating a ␤-catenin-dependent pathway (retrograde signal), the other by blood-borne molecules activating Ras-dependent downstream cascades (anterograde signal). In conclusion, gradients of opposing signaling molecules along the portocentral axis determine the pattern of enzymes and other proteins expressed in hepatocytes of the periportal and pericentral domains of the liver lobule. (HEPATOLOGY 2006;43:407-414.) E ven though the architecture of the liver tissue appears rather uniform, a closer view shows the existence of repetitive small structural and functional units called lobules that compose the liver parenchyma. Hepatocytes within the liver lobule differ in their enzyme content and subcellular structure according to their location relative to the afferent and efferent blood vessels, the terminal branches of the portal and the hepatic (central) veins, respectively (for reviews see 1,2 ). Based on the location of the blood vessels and the direction of the blood flow, the individual liver lobule can therefore 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 key enzymes of the intermediary and xenobiotic metabolism.Two types of zonal patterns of gene expression have been described: one group of genes is stably expressed (non-inducible) within only one or a few layers of hepatocytes of the liver lobule, either pericentral or periportal, whereas a second group of genes displays a more dynamic (inducible) expression that may gradually diminish along the axis of the lobule. 3,4 One of the best-known examples for an enzyme encoded by a member of the first group of genes is glutamine synthetase (GS), which plays a key role in ammonia metabolism. GS is stably expressed at very high levels within only one to two layers of hepatocytes surrounding the central veins, and the number of hepatocytes expressing the enzyme is hardly affected by external stimuli under physiological conditions. 5 Other enzymes, exemplified by key enzymes of carbohydrate metabolism, are also zonally expressed, but in a more gradual pattern. In addition, these latter enzymes undergo dynamic changes in expression as an adaptive response to changes in the hormonal or nutritional status. Xenobiotic metabolizing enzymes, including various cytochromes P450 (CYPs), represent an int...

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…Simultaneous mutation of the β-catenin gene and the tumour suppressor H-ras or p21 by an adenovirus-mediated liver-specific Cre-expression system resulted in 100% tumour incidence with short latency of only several weeks (65). Interestingly, mutations in the β-catenin gene in hepatocellular carcinomas induce overexpression of β-catenin targets such as the glutamine synthetase gene GLUL (66,67), whereas hepatocytes from glutamine synthetase-negative tumours are often H-ras or BRAF mutated and express E-cadherin, reflecting perivenous and periportal profiles, respectively (68). Loss-of-function in APC and Axin is mutually exclusive to CTNNB1 mutations and has been detected in 1-3% and 8-15% of hepatocellular carcinoma cases (for review, see (69)).…”

Zonal gene expression in murine liver: Are tumors helping us to solve the mystery?

“…7 This is also consistent with the early observation that cultured GS-positive hepatocytes maintain their phenotype throughout their lifespan in vitro despite cultivation in media mimicking periportal conditions. 8 The evidence provided by Hailfinger et al 1 concerning periportal signals is less clear. Firstly, the proposed influence of Ras activation was not demonstrated in vitro.…”

“…The first of these would involve soluble factors from the bloodstream inducing Ras activation prevailing in the periportal zone, while the second would consist of an inverse gradient of Wnt signals inducing activation of ␤-catenin prevailing in the pericentral zone. Although this hypothesis is attractive for a number of reasons, the experimental evidence provided by Hailfinger et al 1 does not in itself constitute substantial support.Recent observations have left no doubt that expression of glutamine synthetase (GS), the most pronounced marker enzyme of pericentral cells, 2 is somehow dependent on ␤-catenin signaling. [3][4][5] However, although activation of ␤-catenin seems necessary, it does not appear to be sufficient, since many liver tumors with activated ␤-catenin do not express GS.…”

“…The first of these would involve soluble factors from the bloodstream inducing Ras activation prevailing in the periportal zone, while the second would consist of an inverse gradient of Wnt signals inducing activation of ␤-catenin prevailing in the pericentral zone. Although this hypothesis is attractive for a number of reasons, the experimental evidence provided by Hailfinger et al 1 does not in itself constitute substantial support.…”

“…[3][4][5] However, although activation of ␤-catenin seems necessary, it does not appear to be sufficient, since many liver tumors with activated ␤-catenin do not express GS. The experimental approach taken by Hailfinger et al 1 (to induce pericentral genes in cultured hepatocytes using Wnt factors or inhibitors of GSK3␤) is not conclusive, since whole hepatocyte preparations contain both periportal and pericentral cells of which only the pericentral subpopulation might respond. Moreover, the mechanism by which ␤-catenin signaling might influence GS expression remains obscure, since indication of a permanent activation of ␤-catenin in the GS-positive zone of the lobuli in adult liver is missing.…”