Adult Mouse Liver Research Articles

Three-Dimensional Surface Structure of Macrophages in Fetal and Adult Mouse Liver: An Immunohistochemical Light Microscopic Study

Using 100-µm-thick paraffin sections stained by F4/80 antibody, the three-dimensional surface morphology of macrophages in fetal and adult livers was examined by conventional light microscope equipped with a computer-controlled z-axis stepping motor. Hematopoietic macrophages in fetal livers were located in the center of erythroid cell clusters, forming cell sockets which consisted of two different kinds of projections. The primary cytoplasmic processes were membranous projections and the secondary processes were finger-like projections extending from the primary processes. Erythroids in the cell sockets were linearly arranged on the macrophage surface. Adult sinusoidal macrophages possessed a few pseudopod-like processes, ridge-like profiles and numerous ruffle or spike-like processes, and cell contact with neighboring macrophages could be recognized. Compared to confocal laser scanning microscopy and scanning electron microscopy, this study provided information about cell surface structures at reasonably low cost, although the resolution was limited in z axis due to the stepping interval.

ADAMTS-like 2 (ADAMTSL2) is a secreted glycoprotein that is widely expressed during mouse embryogenesis and is regulated during skeletal myogenesis

ADAMTS-like 2 (ADAMTSL2), is a secreted protein resembling the ancillary domains of the ADAMTS proteases, but with distinct structural features. It has 7 thrombospondin type-1 repeats (TSRs), but an unusually long spacer module, which in both humans and mice, contains a novel insertion bearing six N-glycosylation sites. The ADAMTSL2 protein expressed in HEK293F and COS-1 cells, is a cell-surface and extracellular matrix binding glycoprotein, with N-linked carbohydrate constituting ∼ 20% by mass. The 4.0 kb Adamtsl2 mRNA is found most abundantly in adult mouse liver, lung and spleen by northern blotting. During mouse embryogenesis, Adamtsl2 was expressed most strongly in the third week of gestation. Adamtsl2 mRNA was detected by in situ hybridization in developing skeletal muscle, liver, bronchial and arterial smooth muscle, skin, intervertebral disc, perichondrium, pancreas and spinal cord. Immunohistochemical localization of ADAMTSL2 protein was similar to mRNA expression. Detection of Adamtsl2 mRNA and protein in developing skeletal myotubes, but not undifferentiated myogenic precursors led us to investigate its regulation during in vitro myogenic differentiation. In C2C12 and 23A2 myogenic cells, but not in 23A2 cells rendered non-myogenic by expression of G12V:H-Ras (9A2 cells), differentiation induced by serum starvation triggered expression of Adamtsl2 mRNA, coordinately with Myog, a marker of muscle differentiation. Furthermore, activation of the key myogenic determinant MyoD in 10T1/2 fibroblasts also triggered expression of Adamtsl2 mRNA. Collectively, the data suggest that induction of Adamtsl2 mRNA is an integral feature of myogenesis.

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Von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase.

von Hippel Lindau (VHL) disease is a hereditary cancer syndrome caused by biallelic inactivation of the VHL tumor suppressor gene. The most widely known function of VHL is to limit normoxic protein expression of hypoxia-inducible factor-alpha (HIF-alpha). Loss of the functional VHL gene causes constitutive stabilization of HIF-alpha that primarily up-regulates hypoxia-inducible genes even at normal oxygen concentration, which in turn contribute to VHL tumor progression. We report on the novel function of VHL in hepatic glucose storage and disposal. VHL deletion in adult mouse liver quickly leads to increased accumulation of glycogen granules as well as lipid droplets. This abnormal glycogen storage in VHL-inactivated liver arises at least in part from significantly reduced expression of two key liver-specific glucose metabolism genes, glucose transporter-2 (GLUT2) and glucose-6-phosphatase (G-6-Pase). The expression pattern of these genes in VHL knock-out liver was in contrast to that of well-known HIF target genes, such as PGK, Glut-1, VEGF, and EPO, all of which are highly elevated upon VHL inactivation. Our findings suggest that two distinct signaling pathways exist at the downstream of VHL controlling different sets of gene expression. Following VHL inactivation, one pathway causes oxygen-independent overexpression of classic hypoxia-inducible genes and the other one described here suppresses expression of the genes important for liver glucose metabolism.

Differential age‐ and sex‐dependent hepatic expression of five murine hydroxysteroid sulfotransferases.

Hydroxysteroid sulfotransferases catalyze the sulfonation of hydroxysteroids, bile acids and certain xenobiotics. Recent data suggest that the expression of murine hepatic hydroxysteroid sulfotransferase (Sult2a) is subject to age-and sex-dependent regulation. Although two murine Sult2a cDNAs have been previously described, computational inspection of the mouse genome predicts the presence of five coding Sult2a genes within the same region of chromosome 7. The age- and sex-dependent mRNA expression of the five Sult2a family members were therefore characterized in livers from adult (aged 56 days) and pre-pubertal (21 days) male and female C57BL/6 mice using RT-PCR. The transcripts for two of the Sult2a forms (GenBank accession numbers XM_485863 and XM_894065) were detected in pre-pubertal male and female mouse liver, but not in adult mouse liver from either sex. Two other Sult2a mRNAs (NM_009286 and XM_894052) were expressed in pre-pubertal male and female mouse liver, and in adult female but not male mouse liver. A fifth Sult2a mRNA (XM_983034) was expressed in adult male and female mouse liver, but was not detected in pre-pubertal mouse liver of either sex. These results demonstrate that five Sult2a forms exhibit distinctive patterns of age- and sex-dependent hepatic expression. Supported by ES058223 (M.R.M.), HL50710 (T.A.K) and ES06636.

Enzymatically Active N-Deacetylase/N-Sulfotransferase-2 Is Present in Liver but Does Not Contribute to Heparan Sulfate N-Sulfation

Heparan sulfate (HS) proteoglycans influence embryonic development through interactions with growth factors and morphogens. The interactions depend on HS structure, which is largely determined during biosynthesis by Golgi enzymes. NDST (glucosaminyl N-deacetylase/N-sulfotransferase), responsible for HS N-sulfation, is a key enzyme directing further modifications including O-sulfation. To elucidate the roles of the different NDST isoforms in HS biosynthesis, we took advantage of mice with targeted mutations in NDST1 and NDST2 and used liver as our model organ. Of the four NDST isoforms, only NDST1 and NDST2 transcripts were shown to be expressed in control liver. The absence of NDST1 or NDST2 in the knock-out mice did not affect transcript levels of other NDST isoforms or other HS modification enzymes. Although the sulfation level of HS synthesized in NDST1-/- mice was drastically lowered, liver HS from wild-type mice, from NDST1+/-, NDST2-/-, and NDST1+/- / NDST2-/- mice all had the same structure despite greatly reduced NDST enzyme activity (30% of control levels in NDST1+/- / NDST2-/- embryonic day 18.5 embryos). Enzymatically active NDST2 was shown to be present in similar amounts in wild-type, NDST1-/-, and NDST1+/- embryonic day 18.5 liver. Despite the substantial contribution of NDST2 to total NDST enzyme activity in embryonic day 18.5 liver (approximately 40%), its presence did not appear to affect HS structure as long as NDST1 was also present. In NDST1-/- embryonic day 18.5 liver, in contrast, NDST2 was responsible for N-sulfation of the low sulfated HS. A tentative model to explain these results is presented.

Nephrocan, a Novel Member of the Small Leucine-rich Repeat Protein Family, Is an Inhibitor of Transforming Growth Factor-β Signaling

In a search of new, small leucine-rich repeat proteoglycan/protein (SLRP) family members, a novel gene, nephrocan (NPN), has been identified. The gene consists of three exons, and based on the deduced amino acid sequence, NPN has 17 leucine-rich repeat motifs and unique cysteine-rich clusters both in the N and C termini, indicating that this gene belongs to a new class of SLRP family. NPN mRNA was predominantly expressed in kidney in adult mice, and during mouse embryogenesis, the expression was markedly increased in 11-day-old embryos at a time when early kidney development takes place. In the adult mouse kidney, NPN protein was located in distal tubules and collecting ducts. When NPN was overexpressed in cell culture, the protein was detected in the cultured medium, and upon treatment with N-glycosidase F, the molecular mass was lowered by approximately 14 kDa, indicating that NPN is a secreted N-glycosylated protein. Furthermore, transforming growth factor-beta (TGF-beta)-responsive 3TP promoter luciferase activity was down-regulated, and TGF-beta-induced Smad3 phosphorylation was also inhibited by NPN, suggesting that NPN suppresses TGF-beta/Smad signaling. Taken together, NPN is a novel member of the SLRP family that may play important roles in kidney development and pathophysiology by functioning as an endogenous inhibitor of TGF-beta signaling.

Sodium Barbital Induced Biochemical, Histological and Histochemical Changes in the Liver of Albino Mouse

Introduction:The present work was planned to assess and evaluate some physiological parameters, histopathological and histochemical impacts of sodium barbital on the liver of adult male albino mice. Material and Methods :The mice were divided into 3 groups, the first group served as a control group, while the other two groups were treated with the therapeutic dose (60 mg/kg b.wt., i.p.) for 7 days (short-term group) and 21 days (long-term group) as repeated daily doses. Results: Biochemical analysis showed a significant increase in serum glucose level (hyperglycaemia), AST, ALT and bilirubin, in all treated groups. Also, total lipids and triglycerides showed a significant increase in the long-term group and non significant change in the short-term group. On the other hand, alkaline phosphatase ALP, showed a significant decrease in both treated groups. Total cholesterol level showed a significant decrease in the short-term group but exhibited a significant increase in the long-term group. The results obtained from the present study showed marked alterations in the liver tissue. Histopathological changes in liver tissue were congestion of the central veins, wedening of the blood sinusoids, activation of the phagocytic kupffer cells and cytoplasmic degeneration (fatty and hydropic) with nuclear lesions. Histochemical changes in liver tissue revealed depletion of polysaccharides and total proteins in both short-term and long-term groups. ConclusionSotheseresultscametoconclusionthat barbituratesshouldbeprohibitedand carefully used specially when prescribed as tranquilizer.

Sodium Barbital Induced Biochemical, Histological and Histochemical Changes in the Liver of Albino Mouse

Introduction:The present work was planned to assess and evaluate some physiological parameters, histopathological and histochemical impacts of sodium barbital on the liver of adult male albino mice. Material and Methods :The mice were divided into 3 groups, the first group served as a control group, while the other two groups were treated with the therapeutic dose (60 mg/kg b.wt., i.p.) for 7 days (short-term group) and 21 days (long-term group) as repeated daily doses. Results: Biochemical analysis showed a significant increase in serum glucose level (hyperglycaemia), AST, ALT and bilirubin, in all treated groups. Also, total lipids and triglycerides showed a significant increase in the long-term group and non significant change in the short-term group. On the other hand, alkaline phosphatase ALP, showed a significant decrease in both treated groups. Total cholesterol level showed a significant decrease in the short-term group but exhibited a significant increase in the long-term group. The results obtained from the present study showed marked alterations in the liver tissue. Histopathological changes in liver tissue were congestion of the central veins, wedening of the blood sinusoids, activation of the phagocytic kupffer cells and cytoplasmic degeneration (fatty and hydropic) with nuclear lesions. Histochemical changes in liver tissue revealed depletion of polysaccharides and total proteins in both short-term and long-term groups. ConclusionSotheseresultscametoconclusionthat barbituratesshouldbeprohibitedand carefully used specially when prescribed as tranquilizer.

Catalase activity and rhythmic patterns in mouse brain, kidney and liver

To protect tissues from damaging effects of reactive oxygen species (ROS), organisms possess enzymatic and non-enzymatic antioxidant systems. Cytosolic-enzyme catalase (CAT) is a component of the antioxidant defence system that reduces hydrogen peroxide (H 2O 2) to water (H 2O). The aim of this study was to assess the variation of antioxidant enzyme CAT activity in brain, kidney and liver of adult male mice according to tissue-specific and temporal patterns within a 24-h period (12:12 L/D). The CAT activity was assayed at 4-h intervals. The Cosinor test programme was used to detect and confirm the best corresponding rhythm. In liver, the circadian rhythm of CAT was associated with ultradian components. The prominent circadian rhythm (with a period τ = 24 h) showed a peak located at the middle of the dark phase, more precisely ≅ 17 HALO (Hours After Light Onset). In kidney, only a circadian rhythm of CAT was validated with a peak time located at ≅ 17 HALO. However, in brain, the time pattern of CAT activity showed two peak times at ≅ 1 and ≅ 17 HALO, illustrating the existence of an ultradian rhythm (with a period τ = 12 h). The results showed significant organ differences with the highest activity in liver, compared with kidney (− 89%) and brain (− 98%). This might be related to several factors such as their respective physiological function, the risk of exposure to oxidative damage and the balance between synthesis and degradation of proteins during “normal metabolism”. Moreover, CAT activity revealed differences in time-related changes across a 24-h period that were more obvious in peak levels between the three tissues.

Plasticity of Hepatic Cell Differentiation: Bipotential Adult Mouse Liver Clonal Cell Lines Competent to Differentiate In Vitro and In Vivo

In fetal liver, bipotential hepatoblasts differentiate into hepatocytes and bile duct cells (cholangiocytes). The persistence of such progenitor cells in adult mouse liver is still debated. In damaged liver of adult murine animals, when hepatocyte proliferation is compromised, bipotential oval cells emerge, probably from bile ducts, proliferate, and differentiate to regenerate the liver. However, treatment to elicit oval cell proliferation is not necessary to obtain bipotential stem cells from adult mouse liver. Here, we have isolated bipotential clonal cell lines from healthy liver of 8-10-week-old C57BL/6 mice. Primary cultures established from hepatocyte-enriched suspensions were characterized by time-lapse image acquisition, immunocytology, and RNA transcript analysis. Although hepatocytes dedifferentiated with loss of apical polarity and other hepatocyte markers, they rapidly activated expression of bile duct/oval cell markers. Reversibility of these processes was achieved in part by culture under dilute Matrigel or by aging of confluent cultures. Cell lines were obtained at high frequency from mass cultures, from isolated colonies, and by primary cloning of the hepatocyte-enriched suspension. Cells of the clonal cell lines do not grow in soft agar and are nontumorigenic, and they express cytokeratin 19, A6 antigen, and alpha6 integrin, as well as a large panel of hepatocyte functions. Furthermore, they can participate in liver regeneration in albumin-urokinase-type plasminogen activator/severe combined immune-deficient mice, where they differentiate in clusters of hepatocytes and occasionally bile ducts. These results demonstrate the existence, in normal adult mouse liver, of a significant pool of clonogenic cells that are (or can become) bipotential.

Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice

IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer's disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I(-/-)), resulting in an approximately 80-85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I(-/-) and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I(-/-) mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF(-/-) mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I(-/-) mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I(-/-) mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.

Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways

RNA interference (RNAi) is a universal and evolutionarily conserved phenomenon of post-transcriptional gene silencing by means of sequence-specific mRNA degradation, triggered by small double-stranded RNAs. Because this mechanism can be efficiently induced in vivo by expressing target-complementary short hairpin RNA (shRNA) from non-viral and viral vectors, RNAi is attractive for functional genomics and human therapeutics. Here we systematically investigate the long-term effects of sustained high-level shRNA expression in livers of adult mice. Robust shRNA expression in all the hepatocytes after intravenous infusion was achieved with an optimized shRNA delivery vector based on duplex-DNA-containing adeno-associated virus type 8 (AAV8). An evaluation of 49 distinct AAV/shRNA vectors, unique in length and sequence and directed against six targets, showed that 36 resulted in dose-dependent liver injury, with 23 ultimately causing death. Morbidity was associated with the downregulation of liver-derived microRNAs (miRNAs), indicating possible competition of the latter with shRNAs for limiting cellular factors required for the processing of various small RNAs. In vitro and in vivo shRNA transfection studies implied that one such factor, shared by the shRNA/miRNA pathways and readily saturated, is the nuclear karyopherin exportin-5. Our findings have fundamental consequences for future RNAi-based strategies in animals and humans, because controlling intracellular shRNA expression levels will be imperative. However, the risk of oversaturating endogenous small RNA pathways can be minimized by optimizing shRNA dose and sequence, as exemplified here by our report of persistent and therapeutic RNAi against human hepatitis B virus in vivo.

Transient Appearance of Hepatic Natural Killer Cells with High Cytotoxicity and Unique Phenotype in Very Young Mice

There were few natural killer (NK) cells in the liver in very young mice at the age of 1-2 weeks. This was because the cell yield from the liver of young mice was low. The percentage of NK cells in the liver of young mice, however, was almost comparable with that in the liver of adult mice. Lymphocytes were isolated from the liver and spleen of C57BL/6 (B6) mice, and NK cytotoxicity and phenotype were herein examined in this study. NK cytotoxicity was extremely high in the liver of very young mice. This phenomenon was seen in the liver of various normal mouse strains. In contrast, the appearance of high cytotoxicity was not seen in NK cells of the spleen, irrespective of mouse strains. The quality of NK cells in the liver of young mice was different from that in adult mice. NK cells in the liver of young mice were mainly CD69(+)Mac-1(-) Fas ligand(+), whereas those in the liver of adult mice were CD69(-)Mac-1(+) Fas ligand(-). These results revealed that the quality of hepatic NK cells changes in the process of ageing. Namely, liver NK cells in very young mice temporarily show the highest NK cytotoxicity and a unique activated phenotype. Physiological meaning of the present phenomenon was discussed.

Vitamin-E Supplementation Ameliorates Chromium-and/or Nickel Induced Oxidative Stress in Vivo

The present study was designed to investigate the in vivo effects of nickel chloride [NiCl2; 8, and 16 mg/kg body weight (b wt)] and/or Potassium dichromate (K2Cr2O7; 5 and 10 mg/kg b wt) in the liver of adult mice. The beneficial effects of vitamin E (2 mg/kg) along with their combination were also studied. The antioxidative indices including oxidative lipid peroxidation (LPO) and antioxidative enzymes such as glutathione (GSH), total sulfhydryl (-SH) groups, total ascorbic acid (TAA), superoxide dismutase (SOD) and catalase (CAT) were evaluated in the hepatic tissue using well established techniques. Nickel and/or chromium treatments to mice revealed a significant decline in the levels of these antioxidant parameters as compared to control. Concomitantly a significant increase in lipid peroxidation was obtained. These data indicated that the treatment induced oxidative stress in the hepatic tissue of treated mice, which was more pronounced by combination of metal salts. But supplementation of vitamin E with NiCl2 + K2Cr2O7 to mice exerted no significant alterations in the liver antioxidant system as compared to control, thus indicating its ameliorative role. These findings suggest that vitamin E prevents LPO and protects the antioxidant system in the mouse liver.

Genomic sequence and expression profile of murineBat1aandNfkbil1

In humans, susceptibility to several immunopathologic diseases maps to a conserved block encompassing the polymorphic BAT1, NFKBIL1 (IKBL) and TNF genes in the central MHC. As a pre-requisite for studies of these genes in animal models, we characterized Bat1a and Nfkbil1 in inbred mice differing in their H2 haplotype. We identified two indels and nine single nucleotide polymorphisms (SNP) upstream of Nfkbil1, one indel, nine SNP upstream of Bat1a and a synonymous SNP in exon 2 of Bat1a. H2(g7) and H2(b) mice yielded identical Bat1a and Nfkbil1 sequences. Real time PCR (RT-PCR) showed Bat1a was expressed in adult brain, heart, kidney, liver, lung, pancreas and spleen. Expression of Bat1a was higher in brain and liver of 15-day embryos compared to 1-day old mice and increased moderately in liver and lung of adult mice 2-4 h after LPS challenge. Nfkbil1 expression was low or undetetectable in all tissues and cell lines.

Characterization of Genotoxicity of Kojic Acid by Mutagenicity in Salmonella and Micronucleus Induction in Rodent Liver

Three lots of kojic acid (KA) which were produced for use as a reagent, food additive and in cosmetics were shown to be mutagenic in S. typhimurium TA100 with or without S9 mix, with a specific activity of around 100 revertants per mg of KA. Since there are contradictory reports on genotoxicity of KA, we examined, using HPLC, whether the mutagenicity to S. typhimurium is due to KA itself, or due to contaminants present in the KA samples. Although two UV absorbing fractions were separated by HPLC, mutagenicity was detected only in the major fraction and the specific mutagenic activity of KA did not change before and after HPLC separation. The material in the major peak fractions on HPLC was confirmed to be KA by NMR. Thus it was demonstrated that KA itself is mutagenic and no mutagenic contaminants were detected in the three lots of samples. Since KA is known to produce liver tumors in mice, we further examined the genotoxicity of KA in the liver of rodents. KA induced micronuclei (MN) in the regenerating liver of adult mice by its gastric intubation at 1 g per kg body weight. However, no MN were induced in young mice (3 weeks old) without partial hepatectomy. Since it was recently found that KA had no tumor-initiating activity in the liver of mice in a two-step carcinogenicity study, there is no evidence that the genotoxicity detected in the mouse liver is involved in liver carcinogenesis.

Identification and analysis of novel genes expressed in the mouse embryonic facial primordia

Craniofacial anomalies are a common feature of human congenital dysmorphology syndromes, suggesting that genes expressed in the developing face are likely to play a wider role in embryonic development. To facilitate the identification of genes involved in embryogenesis, we previously constructed an enriched cDNA library by subtracting adult mouse liver cDNA from that of embryonic day (E)10.5 mouse pharyngeal arch cDNA. From this library, 273 unique clones were sequenced and known proteins binned into functional categories in order to assess enrichment of the library (1). We have now selected 31 novel and poorly characterised genes from this library and present bioinformatic analysis to predict proteins encoded by these genes, and to detect evolutionary conservation. Of these genes 61% (19/31) showed restricted expression in the developing embryo, and a subset of these was chosen for further in silico characterisation as well as experimental determination of subcellular localisation based on transient transfection of predicted full-length coding sequences into mammalian cell lines. Where a human orthologue of these genes was detected, chromosomal localisation was determined relative to known loci for human congenital disease.

Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver

The expression of eight mouse hepatic cytochrome P450s (P450s) genes was investigated at the mRNA level in relation with the pattern of growth hormone (GH) administration. The constitutive expression of five sex-dependent P450s was sexually dimorphic, namely female > male for CYP2A4, CYP2B9, CYP2B10, and CYP3A41, and male > female for CYP2D9. In mice neonatally treated with monosodium l-glutamate to produce GH-deficiency, GH was found to be an essential factor with GH archetype as a determinant in the regulatory mechanism of hepatic CYP2D9 and CYP3A41 expression, and GH was shown to be a repressive factor for the constitutive expression in females. Implantation with micro-osmotic pump containing GH (to yield a constant release of GH to mimic the plasma GH profile in females) to male mice increased CYP2A4, CYP2B9, CYP2B10, and CYP3A41, but decreased CYP2D9, expression to female levels, while conversely, twice-daily administration of GH (to produce the so-called male pattern of plasma GH levels) to female mice resulted in the repression of female-specific, CYP2B9 and CYP3A41, as well as female-predominant, CYP2A4 and CYP2B10, expression, and induction of male-specific CYP2D9 expression. Thus, the sex-dependent plasma GH profile (referred to hereafter as the GH archetype) was a decisive factor for the expression of sex-specific P450 genes in adult mouse liver. On the other hand, the regulation of CYP1A2, CYP2C29, and CYP3A11 expression was either sex-independent or GH archetype-independent, considering the comparable levels between sexes of the constitutive expression and GH-inducible expression of these isoforms. Moreover, the observations suggested for the first time that the expression of CYP2B9 and CYP2A4 was not entirely GH-independent, but rather involved an imprinting GH-related factor that participated in the regulatory mechanism of P450 expression in females.

Hedgehog signaling maintains resident hepatic progenitors throughout life

Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.