Differential gene expression in periportal and perivenous mouse hepatocytes

Abstract

Hepatocytes play a pivotal role in both the synthesis and degradation of numerous endogenous biomolecules, thus maintaining metabolic homeostasis, as well as in the conversion and detoxification of xenobiotic compounds. Based on the location of the blood vessels, the terminal branches of the portal and the hepatic (central) veins and on the direction of the blood flow, hepatocytes of each liver lobule can be divided into two subpopulations, an upstream 'periportal' and a downstream 'perivenous' (pericentral) population. Zonal-specific differences in the metabolic capacities of many enzymes or other proteins, and -to a lesser extent ) of their corresponding messenger RNAs, have been subject to extensive studies throughout the last decades.Many enzymes of intermediary metabolism are not distributed uniformly throughout the liver, but are preferentially expressed in either the periportal or the perivenous hepatocyte subpopulation [1][2][3]. Hence, hepatocytes located in either of the two regions have different, often complementary, functions. Whereas, for example, glycolysis is exclusively active in perivenous hepatocytes, key enzymes of gluconeogenesis, the antagonist pathway, are preferentially expressed in periportal hepatocytes [1]. Zonal-specific expression has also been established for enzymes of amino acid and ammonia metabolism, showing, for example, a higher activity of the urea cycle in periportal cells compared to perivenous hepatocytes [3], whereas glutamine synthesis is exclusively active in the perivenous Hepatocytes located in the periportal and perivenous zones of the liver lobule show remarkable differences in the levels and activities of various enzymes and other proteins. To analyze global gene expression patterns of periportal and perivenous hepatocytes, enriched populations of the two cell types were isolated by combined collagenase ⁄ digitonin perfusion from mouse liver and used for microarray analysis. In total, 198 genes and expressed sequences were identified that demonstrated a ‡ 2-fold difference in expression between hepatocytes from the two different zones of the liver. A subset of 20 genes was additionally analyzed by real-time RT-PCR, validating the results obtained by the microarray analysis. Several of the differentially expressed genes encoded key enzymes of intermediary metabolism, including those involved in glycolysis and gluconeogenesis, fatty acid degradation, cholesterol and bile acid metabolism, amino acid degradation and ammonia utilization. In addition, several enzymes of phase I and phase II of xenobiotic metabolism were differentially expressed in periportal and perivenous hepatocytes. Our results confirm previous findings on metabolic zonation in liver, and extend our knowledge of the regulatory mechanisms at the transcriptional level.Abbreviations GS, glutamine synthetase.

Ketohexokinase: Expression and Localization of the Principal Fructose-metabolizing Enzyme

“…Some liver samples displayed strongest immunolabeling around the portal tract, whereas others had more immunolabeling surrounding the central venule. Expression patterns of other metabolic enzymes are known to vary within the hepatic lobule, with some gluconeogenic enzymes more highly expressed around the portal tract, and some glycolytic enzymes around the central venule (Braeuning et al 2006). In mouse and rat kidney, KHK was predominantly localized to the straight segments of the proximal tubules, which lie in medullary rays, extending through the full cortical thickness.…”

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

“…In these studies, gene expression profiles had been analyzed by use of the Affymetrix GeneChip MOE-430A (Affymetrix, Santa Clara, CA) containing approximately 22,600 probe sets including more than 14,000 well characterized mouse genes. Since the criteria for statistical analysis of expression data varied in the two studies, we reevaluated the tumor datasets using as discriminators a log 2 expression ratio Ն1 (equivalent to Ն2-fold change) and a threshold of 0.1 for the false discovery rate-adjusted p values to allow a direct comparison with our data on zonal differences in gene expression in normal liver (for further details see Stahl et al, 2005a,b;Braeuning et al, 2006). The former cutoff was chosen because expression differences smaller than 2-fold are very difficult to detect by quantitative reverse transcription-polymerase chain reaction, which was used in the previous studies for verification of the microarray results.…”

“…Datasets on global mRNA expression patterns in mouse liver tumors mutated in either Ha-ras or Ctnnb1 and datasets on global mRNA expression patterns in perivenous and periportal mouse hepatocytes were available to us from previous experiments conducted in our laboratory (Stahl et al, 2005a;Braeuning et al, 2006). In these studies, gene expression profiles had been analyzed by use of the Affymetrix GeneChip MOE-430A (Affymetrix, Santa Clara, CA) containing approximately 22,600 probe sets including more than 14,000 well characterized mouse genes.…”

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…be chemically induced by carbon tetrachloride (CCl 4 ), which induces oxidative damages through conversion of CCl 4 to the trichloromethyl radical • CCl3 by Cyp2E1, a pericentral hepatocyte-specific enzyme (39,40). We next evaluated whether the human transcriptomic signatures associated with pathological features of NASH are recapitulated in mice fed a HFD/MCDD.…”