Regulation Of Genes In Liver Research Articles

Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion

Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein β. Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration.

Correlation analysis between gene expression profile of high‐fat emulsion‐induced non‐alcoholic fatty liver and liver regeneration in rat

To explore the relevance of non-alcoholic fatty liver disease (NAFLD) to liver regeneration (LR), rat models of non-alcoholic steatohepatitis (NASH) and LR were established, respectively, then Rat Genome 230 2.0 Array was used to detect the gene expression abundance of them, and the reliabilities of the array data were confirmed by real-time RT-PCR. As a result, the expression of 93 genes was significantly changed during NAFLD occurrence and 948 genes in LR. Hierarchical clustering indicated that the expression profiles of the above two events were quite different. K-means cluster classified their expression patterns into four clusters, and gene expression trends of clusters 1, 2 were similar in NAFLD and LR, while clusters 3, 4 were contrary with the gene expression changes of LR more abundant. DAVID classifications and functional enrichment analysis found that lipid metabolism and carbohydrate metabolism were stronger in NAFLD than in LR, but some other physiological activities including inflammation/immune response, cell adhesion, and migration, cell proliferation and differentiation in NAFLD were weaker than in LR. IPA further indicated that lipid metabolism, inflammation response, and cellular development were highly associated with NAFLD, and thus identified some potential biomarkers for NAFLD.

Gene expression profiles reveal significant differences between rat liver cancer and liver regeneration

Rapid cell proliferation and growth occur in both liver cancer (LC) and liver regeneration (LR). Does it imply that LC and LR share some similar molecular mechanisms? To elucidate the intrinsic similarities and differences between the above two processes at transcriptional level, rat models of diethylnitrosamine-induced LC and 2/3 partial hepatectomy-induced LR were separately established. Then Rat Genome 230 2.0 Array was used to detect gene expression profiles of liver tissues obtained from the above two models, and bioinformatics methods, such as hierarchical clustering, k-means clustering and Expression Analysis Systematic Explorer (EASE), were applied to uncover the correlation between gene expression changes and physiological activities in LC and LR. Subsequently expression changes of six selected genes were confirmed by real-time quantitative RT-PCR. As a result, the expressions of 909 genes were found significantly changed during LC occurrence and 948 genes in LR. The expression profiles of the above two events were extremely different, and their expression patterns were classified into 6 clusters. Based on the correlation between expression patterns and functional profiles, we found that drug/toxin metabolism and oxidation reduction were induced in LC, but decreased in LR at the transcription level, while lipid, steroid and chemical homeostasis were remarkably repressed in LC but induced in LR; inflammation/immune response and apoptosis were not obvious or weaker in LC than in LR, whereas the activities of angiogenesis and cell adhesion/migration in LC were much stronger.

Regulation of xenobiotic transporter genes in liver and brain of juvenile thicklip grey mullets (Chelon labrosus) after exposure to Prestige-like fuel oil and to perfluorooctane sulfonate

Xenobiotic transport proteins are involved in cellular defence against accumulation of xenobiotics participating in multixenobiotic resistance (MXR). In order to study the transcriptional regulation of MXR genes in fish exposed to common chemical pollutants we selected the thicklip grey mullet (Chelon labrosus), since mugilids are widespread in highly degraded estuarine environments where they have to survive through development and adulthood. Partial sequences belonging to genes coding for members of 3 different families of ATP binding cassette (ABC) transporter proteins (ABCB1; ABCB11; ABCC2; ABCC3; ABCG2) and a vault protein (major vault protein, MVP) were amplified and sequenced from mullet liver. Their liver and brain transcription levels were examined in juvenile mullets under exposure to perfluorooctane sulfonate (PFOS) and to fresh (F) and weathered (WF) Prestige-like heavy fuel oil for 2 and 16days. In liver, PFOS significantly up-regulated transcription of abcb1, abcb11 and abcg2 while in brain only abcb11 was up-regulated. Both fuel treatments significantly down-regulated abcb11 in liver at day 2 while abcc2 was only down-regulated by WF. mvp was significantly up-regulated by F and down-regulated by WF at day 2 in the liver. At day 16 only a significant up-regulation of abcb1 in the F group was recorded. Brain abcc3 and abcg2 were down-regulated by both fuels at day 2, while abcb1 and abcc2 were only down-regulated by F exposure. After 16days of exposure only abcb11 and abcg2 were regulated. In conclusion, exposure to organic xenobiotics significantly alters transcription levels of genes participating in xenobiotic efflux, especially after short periods of exposure. Efflux transporter gene transcription profiling could thus constitute a promising tool to assess exposure to common pollutants.

Regulator of G Protein Signaling (RGS16) Inhibits Hepatic Fatty Acid Oxidation in a Carbohydrate Response Element-binding Protein (ChREBP)-dependent Manner

G protein-coupled receptor (GPCR) pathways control glucose and fatty acid metabolism and the onset of obesity and diabetes. Regulators of G protein signaling (RGS) are GTPase-activating proteins (GAPs) for G(i) and G(q) α-subunits that control the intensity and duration of GPCR signaling. Herein we determined the role of Rgs16 in GPCR regulation of liver metabolism. Rgs16 is expressed during the last few hours of the daily fast in periportal hepatocytes, the oxygen-rich zone of the liver where lipolysis and gluconeogenesis predominate. Rgs16 knock-out mice had elevated expression of fatty acid oxidation genes in liver, higher rates of fatty acid oxidation in liver extracts, and higher plasma β-ketone levels compared with wild type mice. By contrast, transgenic mice that overexpressed RGS16 protein specifically in liver exhibited reciprocal phenotypes as well as low blood glucose levels compared with wild type littermates and fatty liver after overnight fasting. The transcription factor carbohydrate response element-binding protein (ChREBP), which induces fatty acid synthesis genes in response to high carbohydrate feeding, was unexpectedly required during fasting for maximal Rgs16 transcription in liver and in cultured primary hepatocytes during gluconeogenesis. Thus, RGS16 provides a signaling mechanism for glucose production to inhibit GPCR-stimulated fatty acid oxidation in hepatocytes.

Postprandial transcriptome associated with virgin olive oil intake in rat liver

Liver has been proposed as a gatekeeper that regulates postprandial lipemia and a potential target for regulation by acute intake of virgin olive oil. To characterize the hepatic gene expression response to a fat gavage, male rats were fed a bolus of 5 ml of extra-virgin olive oil and the hepatic mRNA expression analyzed 4 hours later using DNA microarrays. To provide an initial screening of candidate genes, only twenty one with remarkably modified expression between both conditions (signal log2 ratio > 2.5 or < -2.5) were considered and confirmed by quantitative real time PCR. Those that presented biological significance were also analyzed 8 hours after the experimental approach. Hepatic A2m Slc13a5 and Nrep mRNA expressions were found significantly changed in both studied conditions and showed the highest significant associations with postprandial plasma triglycerides and lack of association with basal triglyceridemia. These results highlight new gene regulation in liver by postprandial triglyceridemia and will help to understand the complex human pathology providing the involvement of hepatic proteins and new strategies to cope with postprandial metabolism.

Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver

Little is known about the role of the transcription factor peroxisome proliferator-activated receptor (PPAR) beta/delta in liver. Here we set out to better elucidate the function of PPARbeta/delta in liver by comparing the effect of PPARalpha and PPARbeta/delta deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARalpha and PPARbeta/delta deletion was similar, whereas in fasted state the effect of PPARalpha deletion was much more pronounced, consistent with the pattern of gene expression of PPARalpha and PPARbeta/delta. Minor overlap was found between PPARalpha- and PPARbeta/delta-dependent gene regulation in liver. Pathways upregulated by PPARbeta/delta deletion were connected to innate immunity and inflammation. Pathways downregulated by PPARbeta/delta deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPARbeta/delta-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARbeta/delta target genes. In contrast to PPARalpha-/- mice, no changes in plasma free fatty acid, plasma beta-hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPARbeta/delta-/- mice. Our data indicate that PPARbeta/delta governs glucose utilization and lipoprotein metabolism and has an important anti-inflammatory role in liver. Overall, our analysis reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver.

EXPRESSION PROFILES OF THE CELL MIGRATION-ASSOCIATED GENES DURING RAT LIVER REGENERATION

Cell migration plays the essential role in embryogenesis, wound healing, immunization, infection, and cancer metastasis. To study actions of cell migration-associated genes in liver regeneration, these genes were obtained by seaching for the related databases and literatures, and comprehensive analysis for the gene expression change during the regenerating process in liver was detected by Rat Genome 230 2.0 array, and identification of the LR-associated genes was through comparing the discrepancy in gene expression between sham operation and partial hepatectomy groups. The initially and totally expressed numbers of these genes in the initial phase of LR, G0/G1 transition, cell proliferation, cell differentiation, and structural-functional reconstruction were 88, 16, 79, 9, and 177, 90, 632, 207, respectively, illustrating that the associated genes triggered their expression mainly in the priming stage, and worked in different phases. Their expression similarity was classified into five groups and their expression patterns were categorized into 38 types, and the overall times of up-regulation and down-regulation were 589 and 427. Based on expression profiles and expression patterns of cell migration-associated genes in LR, it was confirmed that cell migration-associated genes rise in mRNA levels.

Expression profiles of the extracellular matrix-associated genes during rat liver regeneration

It has been well known that the extracellular matrix (ECM) plays an important role in cell polarization, cell adhesion, cell proliferation, morphogenesis and differentiation. For the sake of the further in-depth investigation of the changes and actions of ECM in liver regeneration (LR) at gene transcriptional level, the ECM-associated genes were obtained by databases searching and literature retrieving, subsequently their expression profiles in rat regenerating liver were detected using Rat Genome 230 2.0 array, then LR-associated genes were identified based on comparison of the gene expression difference between sham operation (SO) group and partial hepatectomy (PH) group. A total of 97 genes were verified to be LR-associated. The initially and totally expressed number of these genes occurring in initial phase of LR, G0/G1 transition, cell proliferation, cell differentiation and structure-functional reconstruction were 49, 19, 43, 5 and 84, 51, 369, 144, respectively, illustrating that expression of the ECM-associated genes were initiated mainly in the early phase, working in differ-ent phases. Their expression similarity was classified into 5 groups including only up-, predominantly up-, only down-, predominantly down-, and equal in up-regulated and down-regulated, involving 38, 21, 21, 10 and 7 genes, respectively; the number of up-regulated expressed genes and down-regulated expressed ones was 411 and 186; their expression patterns were categorized into 24 types, showing that the physiological and biochemical activities in LR were characterized by phase, diversity and intricacy. According to expression profiles and expression patterns of the ECM-associated genes in LR, it was confirmed that the levels of the below-listed genes in expression increased at the corresponding phases of LR, including fibronectin-associated genes at early phase in LR, and collagen-associated genes at middle phase.

Regulation of Cholesterol Biosynthetic Genes by the EGR Family of Transcription Factors

Recent work has shown that the Egr2 transcription factor plays a direct role in inducing transcription of cholesterol biosynthetic genes during myelination of peripheral nerves. Myelination requires a considerable amount of de novo cholesterol synthesis in Schwann cells, and mice lacking Egr2 show a decrease in cholesterol biosynthetic gene transcription despite little change in SREBP levels. To determine if Egr family members play a similar role in other tissues, we have investigated the role of Egr1 in regulation of cholesterol biosynthetic genes in liver. Egr1 is induced by insulin both in vitro and in vivo, and therefore could mediate the insulin‐dependent induction of hepatic cholesterol biosynthesis. Using chromatin immunoprecipitation assays, we have shown a &gt;4‐fold insulin‐dependent increase in Egr1 binding to the Hmgcr and Cyp51 promoters in the H4IIE liver cell line. The analysis has been extended to detection of Egr1 binding to promoters in liver, which reveals a &gt;5‐fold induction in Egr1 binding to the Hmgcr and Mod1 promoters in mouse liver in response to feeding as well as an increase in expression of these genes. Overall, we have identified Egr1 as a potential regulator of hepatic cholesterol biosynthesis. This work was supported by a grant from the American Heart Association, 0650102Z.

Expression profiles of the genes associated with metabolism and transport of amino acids and their derivatives in rat liver regeneration

Amino acids (AA) are components of protein and precursors of many important biological molecules. To address effects of the genes associated with metabolism and transport of AA and their derivatives during rat liver regeneration (LR), we firstly obtained the above genes by collecting databases data and retrieving related thesis, and then analyzed their expression profiles during LR using Rat Genome 230 2.0 array. The LR-associated genes were identified by comparing the gene expression difference between partial hepatectomy (PH) and sham-operation (SO) rat livers. It was approved that 134 genes associated with metabolism of AA and their derivatives and 26 genes involved in transport of them were LR-associated. The initially and totally expressing number of these genes occurring in initial phase of LR (0.5-4 h after PH), G0/G1 (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction of liver tissue (72-168 h after PH) were respectively 76, 17, 79, 5 and 162, 89, 564, 195, illustrating that these LR-associated genes were initially expressed mainly in initial stage, and functioned in different phases. Frequencies of up-regulation and down-regulation of them being separately 564 and 357 demonstrated that genes up-regulated outnumbered those down-regulated. Categorization of their expression patterns into 22 types implied the diversity of cell physiological and biochemical activities. According to expression changes and patterns of the above-mentioned genes in LR, it was presumed that histidine biosynthesis in the metaphase and anaphase, valine metabolism in the anaphase, and metabolism of glutamate, glutamine, asparate, asparagine, methionine, alanine, leucine and aromatic amino acid almost were enhanced in the whole LR; as for amino acid derivatives, transport of neutral amino acids, urea, gamma-aminobutyric acid, betaine and taurine, metabolism of dopamine, heme, S-adenosylmethionine, thyroxine, and biosynthesis of hydroxyproline, nitric oxide, orinithine, polyamine, carnitine, selenocysteine were augmented during the entire liver restoration. Above results showed that metabolism and transport of AA and their derivates were necessary in liver regeneration.

Inducibility of AhR-regulated CYP genes by β-naphthoflavone in the liver, lung, kidney and heart of the pig

The presence and inducibility of CYP enzymes belonging to the family 1 (CYP 1A1, 1A2 and 1B1) and AhR have been studied in liver, lung, kidney and heart of control and beta-naphthoflavone (βNF)-treated pigs. Segments of so far undescribed genes for porcine CYP 1A2, 1B1 and AhR were identified by RT-PCR and their sequences found to be highly homologous to those of the corresponding human genes. The mRNA level of CYP 1A1 was induced by βNF, although to a different extent, in liver, lung, kidney and heart. This transcriptional activation of CYP 1A1 was accompanied in microsomes of all these organs by an induction of 7-ethoxyresorufin deethylase activity (a marker of this isoform) and an increase in a protein band immunoreactive with anti-rat CYP 1A1. An increase in CYP 1A2 transcription and in activity of microsomal 7-methoxyresorufin demethylase and acetanilide 4-hydroxylase (both markers of 1A2) was observed in the liver and, to a very small extent, in the lung but not in kidney and heart. As to CYP 1B1, its transcription was detected in liver, lung and heart only following the βNF treatment; however this mRNA expression did result in any detectable microsomal 17β-estradiol 4-hydroxylase activity (a marker of this isoform). The CYPs induced by βNF were further investigated by using some other marker activities. It was found that porcine CYP 1A1 and 1A2, unlike the human counterparts, could only deethylate 7-ethoxycomarin to a very small extent, if at all, whereas 7-ethoxy 4-trifluoromethylcoumarin was a good substrate for pig CYP 1A1. Overall, our results demonstrated a differential expression and regulation of the AhR-mediated CYP genes in liver, lung, kidney and heart of the pig.naphthoflavone

Hepatocyte Nuclear Factor (HNF) 1 and HNF4 Mediate Hepatic Multidrug Resistance Protein 2 Up-Regulation during Hepatitis C Virus Gene Expression

Hepatitis C virus (HCV) is known to induce hepatic oxidative stress that is implicated in the up-regulation of multidrug resistance proteins (MRPs). The relationship between increased prooxidant production, MRPs, and HCV has not been investigated. Here, we report that a homeodomain-containing transcription factor, hepatocyte nuclear factor (HNF) 1, plays a central role in liver gene regulation during HCV gene expression and/or subgenome replication. MRP2 protein and mRNA expression were increased and MRP2 promoter activity was increased 7-fold. Mutations within the putative HNF1 binding site of the human MRP2 promoter abrogated HCV-induced activation, implicating HNF1 in the induction of MRP2 by HCV. The mechanism by which HNF1-mediated activation occurs seems to be transcriptional, because the regulated expression of HNF4, which is known to control HNF1 expression, was also increased. Consistent with this finding, HNF1 mRNA was increased 10-fold. A promoter-luciferase construct of the human HNF1 gene was activated in an HNF4-dependent manner, and a mutant construct lacking the HNF4 binding site was not activated in HCV-positive cells. Consistent with this hypothesis, HNF4 protein and mRNA levels as well as HNF4 promoter activity and DNA binding activity were increased. The expression of HNF1 seems to play a critical role in the induction of hepatic MRP2 secondary to HCV subgenomic replication. The ability of HCV to induce HNF1 and HNF4 is attributed to 1) increased oxidative stress and 2) direct protein-protein interactions between HCV nonstructural component (NS) 5A and HNF1, leading to enhanced HNF1 DNA binding. In conclusion, we describe a novel mechanism by which HCV gene expression may induce adaptive responses involving MRP2 via HNF1 activation. This may constitute, in part, the cellular detoxification task force during HCV infection.

A common set of immediate-early response genes in liver regeneration and hyperplasia

Partial hepatectomy (PH) and some tumor-promoting agents stimulate hepatocyte cell proliferation, but each treatment acts through distinct transcription factors. We compared mouse immediate-early gene expression changes after PH with those induced by 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene (TCPOBOP), a tumor-promoting liver mitogen. PH activates nuclear factor κB (NF-κB) and Stat3, whereas TCPOBOP is a ligand for the nuclear receptor, constitutive androstane receptor (CAR). RNA from 1 and 3 hours after each treatment was hybridized to a 9,000 complementary DNA (cDNA) microarray. Of about 6,000 messenger RNAs that had detectable expression, 127 showed reproducible up-regulation or down-regulation at a significant level. The TCPOBOP response was more discrete than the PH response; they amounted to 1% and 1.9% of positive hybridizations, respectively. Twenty-three genes were regulated only by TCPOBOP, 57 only by PH, and 59 by both treatments. More detailed analysis defined 16 clusters with common patterns of expression. These patterns and quantification of hybridization levels on the array were confirmed by Northern blots. TCPOBOP selectively activated expression of a number of detoxification enzymes. In conclusion, the genes that were regulated by both treatments suggest down-regulation of apoptosis, altered signal transduction, and early biogenesis of critical cell components. (H epatology 2003;38:314-325.)

Liver-Enriched Transcription Factors in Liver Function and Development. Part I: The Hepatocyte Nuclear Factor Network and Liver-Specific Gene Expression

Numerous studies have established the pivotal role of liver-enriched transcription factors in organ development and cellular function, and there is conclusive evidence for transcription factors to act in concert in liver-specific gene expression. During organ development and in progenitor cells the timely expression of certain transcription factors is necessary for cellular differentiation, and there is overwhelming evidence for hierarchical and cooperative principles in a networked environment of transcription factors. The search for molecular switches that control stem cell imprinting and liver-specific functions has lead to the discovery of many interactions between such different molecules as transcription factors, coactivators, corepressors, enzymes, DNA, and RNA. Many of these interactions either repress or activate liver-specific gene expression. It thus can be demonstrated that specific mutational changes in liver-enriched transcription factors lead to altered intermolecular interactions with the consequence of human disease. This review provides an overview of our current knowledge about liver-enriched transcription factors and their role in liver function and development. We review the basic principles of gene transcription, the role of liver-enriched transcription factors in liver gene regulation, and the classification of transcription factors by their DNA-binding domains.

Liver gene regulation in rats following both 70 or 90% hepatectomy and endotoxin treatment.

The metabolic state effect of liver failure on liver gene regulation was evaluated in a rat model. Following 70 or 90% hepatectomy and lipopolysaccharide or vehicle treatment at intervals up to 24 h, the liver remnants were analyzed for mRNA levels for acute-phase, liver-specific and growth-related proteins. After 70% hepatectomy mRNA for alpha 1-acid glycoprotein, alpha 2-macroglobulin, thiostatin and fibrinogen, haptoglobin increased three- to sevenfold (P < 0.05), and mRNA for cyclin D and histone 3 increased seven- and 15-fold (P < 0.05), respectively. After lipopolysaccharide injection and 70% hepatectomy were done, mRNA for acute-phase proteins raised significantly (P < 0.05), more to five to 20-fold, while mRNA for growth-related proteins raised significantly (P < 0.05) less to three- to fourfold. After 90% hepatectomy, acute-phase protein mRNA increased five- to ninefold (P < 0.05) more than after 70% hepatectomy, while mRNA for histone 3 and cyclin D did not increase within 24 h, which indicates a delayed growth after 90% hepatectomy. In 90% of hepatectomized rats treated with lipopolysaccharide, acute-phase protein mRNA raised three- to sixfold (P < 0.05) less than after vehicle treatment. In endotoxemia from liver failure, the synthesis of acute-phase proteins is upregulated by gene regulation at the expense of that for regeneration, which may be an appropriate response for immediate survival. In severe liver failure, endotoxin may interfere with the appropriate gene regulation.

Host liver gene regulation during chronic infection with the hepatitis C virus

Host liver gene regulation during chronic infection with the hepatitis C virus

Host liver gene regulation during chronic infection with the hepatitis C virus

Host liver gene regulation during chronic infection with the hepatitis C virus

PRL-1 PTPase expression is developmentally regulated with tissue-specific patterns in epithelial tissues.

The mechanisms controlling tyrosine phosphorylation of cellular proteins are important in the regulation of many cellular processes, including development and differentiation. Protein tyrosine phosphatases (PTPases) may be as important as protein tyrosine kinases (PTKs) in these processes. PRL-1 is a distinct PTPase originally identified as an immediate-early gene in liver regeneration whose expression is associated with growth in some tissues but with differentiation in others. We now demonstrate that the PRL-1 protein is expressed during development in a number of digestive epithelial tissues. It is expressed at variable time points in the developing intestine, but its expression is limited to the developing villus enterocytes. In the gastric epithelium, PRL-1 expression in the adult is restricted to zymogen cells. PRL-1 is also expressed in the developing liver and esophagus and in the epithelia of the kidney and lung. In each of these contexts, the expression of PRL-1 is associated with terminal differentiation, suggesting that it may play a role in this important developmental process.

The augmenter of liver regeneration induces mitochondrial gene expression in rat liver and enhances oxidative phosphorylation capacity of liver mitochondria.

The mammalian augmenter of liver regeneration gene encodes a protein involved in the unique process of liver regeneration. The augmenter of liver regeneration respective protein stimulates hepatocyte proliferation in hepatectomized rats and inhibits cytotoxic activity of liver-derived Natural Killer cells from intact rats. Augmenter of liver regeneration protein shares homology with a Saccharomyces Cerevisiae protein essential for the viability, oxidative phosphorylation and cell-division cycle. To demonstrate if augmenter of liver regeneration protein, like the homologous in the yeast, plays a role in the regulation of biogenesis of mitochondria. Augmenter of liver regeneration protein was injected in intact rats and, in the hepatic tissue, the expression of two genes located in two different regions of the mitochondrial genome, mitochondrial ATPase 6/8, and ND1 subunit, and of a nuclear gene, mitochondrial Transcription Factor A, were considered. In addition, cytochrome content and oxidative phosphorylation capacity of liver-derived mitochondria were evaluated. The augmenter of liver regeneration protein administration induces an increase in the mitochondrial gene expression and enhances cytochrome content and oxidative phosphorylation capacity of liver-derived mitochondria. The present data demonstrate a comparable role in the regulation of mitochondria biogenesis in the eukaryotic cell like the yeast protein. This phenomenon could be part of the complex mechanism through which augmenter of liver regeneration regulates hepatocyte proliferation.