Characterization of enzymes involved in formation of ethyl esters of long-chain fatty acids in humans.

Elevated fatty acid ethyl ester (FAEE) concentrations have been detected in postmortem organs from alcoholics and patients acutely intoxicated by alcohol, and FAEE have been implicated as mediators of ethanol-induced organ damage. The formation of FAEE is catalyzed by acyl-coenzyme A:ethanol O-acyltransferase (AEAT) and by FAEE synthase, which utilize acyl-CoA and free fatty acids, respectively, as substrates. Because little is known about the capacity of various human tissues to synthesize and hydrolyze FAEE, we investigated formation of FAEE by AEAT and FAEE synthase in tissue homogenates from human gastric ventricular and duodenal mucosa, pancreas, liver, heart, lung, and adipose tissue, gallbladder mucosa, and in serum. Liver, duodenal mucosa, and pancreas were found to have the highest capacities to synthesize FAEE, mainly due to AEAT. FAEE hydrolyzing activity was highest in liver and pancreas, but hardly detectable in adipose tissue or heart. Because fatty acids and alcohol are absorbed by the intestinal mucosa, intestine may be a major site of FAEE synthesis, and FAEE may be delivered via the circulation to other organs and taken up by lipoprotein receptor-mediated uptake. A very low rate of FAEE hydrolysis was detected in heart and adipose tissue, which probably accounts for the previously observed accumulation of FAEE in these organs.     

The presence of mercury selenide in various tissues of the striped dolphin: evidence from μ-XRF-XRD and XAFS analyses

Marine mammals accumulate mercury in their tissues at high concentration and detoxify by forming mercury selenide (HgSe, tiemannite) mainly in the liver. We investigated the possibility of formation of HgSe in various tissues (liver, kidney, lung, spleen, pancreas, muscle and brain) other than the liver of the striped dolphin (Stenella coeruleoalba). We applied a combination method of micro-X-ray fluorescence (μ-XRF) imaging and micro-X-ray diffraction (μ-XRD) using a synchrotron radiation X-ray microbeam to analyze the tissue samples directly with minimal sample preparation. By this method, many accumulation points for Hg and Se on a micron scale were found in thin sections of the spleen and liver tissue and consequently, the XRF spectra and the XRD pattern of the hot spots confirmed the presence of tiemannite, HgSe. On the other hand, the insoluble fractions after enzyme digestion of the nuclear and mitochondrial fractions of all tissues were subjected to X-ray absorption fine structure (XAFS) analysis. XAFS analysis confirmed the presence of HgSe in all the tissues examined (liver, kidney, lung, spleen, pancreas, muscle and brain) of the striped dolphin. The presence of HgSe in all the tissues examined suggests that Se would be involved in the detoxification process of Hg in various tissues other than the liver. This contribution seems to be large especially in the liver and spleen but relatively small in the kidney, pancreas and brain, because the proportion of insoluble fraction containing HgSe was lower in these tissues (25 to 46%). This is the first report on the presence of tiemannite HgSe in various tissues of marine mammals.     

Blood vessels restrain pancreas branching, differentiation and growth

How organ size and form are controlled during development is a major question in biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here, we report that, surprisingly, non-nutritional signals from blood vessels act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus, the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells.     

Effect of manganese poisoning on the levels of manganese and iron in rat viscera

Twenty rats were poisoned by manganese inhalation, and sacrificed six months after the first exposure. The tissue concentrations (in microgram/g dry weight) of manganese and iron were found in liver, pancreas, lung, kidney and suprarenal gland for atomic absorption spectrometry in control and experimental animals. The measurements show high tissue concentrations of manganese, especially in liver and pancreas of the experimental animals, as well as a little increase in the tissue concentrations of iron, fundamentally in liver, kidney and suprarenal gland.     

Evidence for a common cell of origin for primitive epithelial cells isolated from rat liver and pancreas.

The appearance of differentiated hepatocytes in the adult rat pancreas as well as pancreatic-type tissue in the adult rat liver can be experimentally induced (Reddy et al.: J. Cell Biol., 98:2082-2090, 1984; Rao et al., J. Histochem. Cytochem., 34:197-201, 1986). These observations suggest a lineage relationship between cell compartments present in rat liver and pancreas. The present data demonstrate that epithelial cell lines with almost identical phenotypes can be established from adult rat liver and pancreas. The established cell lines showed similar morphologies as established by light- and electron-microscopic studies. The cell lines showed a unique expression pattern of intermediate filament proteins. Vimentin, actin, and beta-tubulin were present in all cell lines. In addition, simple epithelial type II cytokeratins 7 and 8 were found to be coexpressed with the type I cytokeratin 14 in several of the cell lines. Neither the type I cytokeratins 18 and 19, which are the normal partners for cytokeratins 8 and 7 in filament formation, nor the type II cytokeratin 5 could be detected despite the fact that filaments were formed by both cytokeratins 8 and 14. This suggests that cytokeratin 14 acts as an indiscriminate type I cytokeratin in filament formation in the established cell lines. The cell lines expressed the same sets of LDH and aldolase isoenzymes and identical sets of glutathione transferase subunits. In addition, the epithelial cell lines from liver and pancreas were equally sensitive to the growth-inhibitory effects of TGF-beta 1. No expression of tissue- or cell-specific proteins such as alpha-fetoprotein, albumin, amylase, elastase, or gamma-glutamyl transpeptidase were detected. The almost identical phenotypes of the hepatic and pancreatic cell lines suggest that they may be derived from a common primitive epithelial cell type present in both rat liver and pancreas. In contrast to parenchymal cells, these cells have an extended capacity for proliferation in vitro and may represent a progeny from a "precursor" or "stem" cell compartment in vivo.     

A bipotential precursor population for pancreas and liver within the embryonic endoderm

The pancreas emerges independently from dorsal and ventral domains of embryonic gut endoderm. Gene inactivation experiments in mice have identified factors required for dorsal pancreas development, but factors that initiate the ventral pancreas have remained elusive. In this study, we investigated the hypothesis that the emergence of the ventral pancreas is related to the emergence of the liver. We find that the liver and ventral pancreas are specified at the same time and in the same general domain of cells. Using embryo tissue explantation experiments, we find that the default fate of the ventral foregut endoderm is to activate the pancreas gene program. FGF signalling from the cardiac mesoderm diverts this endoderm to express genes for liver instead of those for pancreas. No evidence was found to indicate that the cell type choice for pancreas or liver involves a selection for growth or viability. Cardiac mesoderm or FGF induces the local expression of sonic hedgehog, which in turn is inhibitory to pancreas but not to liver. The bipotential precursor cell population for pancreas and liver in embryonic development and its fate selection by FGF has features that appear to be recapitulated in the adult pancreas and are reflected in the evolution of these organs.     

Histology and ultrastructure of the hepatopancreas of the tigerfish,Hydrocynus forskahlii

Study of the histology and ultrastructure of the hepatopancreas of the tigerfish, Hydrocynus forskahlii shows that the liver parenchyma is divided into irregularly shaped lobules, separated by the exocrine pancreas and associated connective tissue. The hepatocytes are arranged in interconnecting cords or laminae, two to three cell layers in thickness. Sinusoids separate the laminae. The spherical to oval-shaped hepatocytes contain large, round, centrally situated nuclei with prominent nucleoli. The cytoplasm of the hepatocytes contains abundant rough and smooth endoplasmic reticulae, free polysomes, and mitochondria. Exocrine pancreatic tissue is scattered throughout the liver. This tissue is encapsulated by an endothelium resting on a thin layer of connective tissue and is separated from the liver parenchyma by a sinusoid. The nuclei of the exocrine pancreas cells are spherical, basally situated within the cells, and contain dark nucleoli. Vesicular rough endoplasmic reticulae and secretory granules lie in the apical regions of the exocrine pancreas cells. © 1996 Wiley-Liss, Inc.     

Evidence for inhibitors of the cell surface protease guanidinobenzoatase

Guanidinobenzoatase is a protease present on the surface of tumour cells. The present study describes the isolation of a protein inhibitor of guanidinobenzoatase obtained from extracts of liver and pancreas and purified by affinity techniques. Pancreatic acinar cells have been shown to possess a latent form of guanidinobenzoatase and this latency is due to complex formation with the inhibitor. A fluorescent marker has been employed to demonstrate the presence or absence of the inhibitor on sections of pancreatic tissue. The inhibitor has been shown to be exchangeable with liver and pancreatic inhibitors obtained from different species. It is postulated that these inhibitors may play a role in enzyme control.     

柴芩承气汤对重症急性胰腺炎并发肝损伤大鼠的治疗作用及其机制

目的：研究柴芩承气汤（CQCQD）对重症急性胰腺炎（SAP）并发肝损伤大鼠的治疗作用及其机制。方法：72只SD大鼠随机分为3组（n=24）：假手术（sham）组,重症急性胰腺炎模型（SAP）组和柴芩承气汤治疗（CQCQD）组。去氧胆酸钠胰胆管逆行注射建立SAP大鼠模型,CQCQD组给予柴芩承气汤治疗,于造模后1 h、5 h、10 h观察各组不同时间点的胰腺、肝脏组织病理学变化,检测血清中淀粉酶（AMS）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）活性、白介素-6（IL-6）水平及胰腺、肝脏组织单核细胞趋化蛋白-1（MCP-1）和IL-6 mRNA的表达情况。结果：与sham组比较,SAP组血清AMS、ALT、AST活性及IL-6水平明显升高,胰腺、肝脏组织MCP-1及IL-6 mRNA表达升高（P<0.05）;与SAP组比较,CQCQD组血清AMS、ALT、AST活性及IL-6水平明显降低;胰腺和肝脏组织病理损伤减轻,胰腺、肝脏组织MCP-1及IL-6 mRNA表达明显减弱（P<0.05）。结论：MCP-1参与了SAP并发肝损伤的进展;柴芩承气汤能显著抑制胰腺、肝脏组织MCP-1的表达,减轻SAP时胰腺、肝脏组织病理损伤,对SAP并发肝损伤起到治疗作用。     

Glutamine-dependent asparagine synthetase in fetal, adult and neoplastic rat tissues.

Three enzyme reactions related to asparagine synthesis were studied in rat tissues: formation of aspartylhydroxamate, either from aspartate or by transfer from asparagine, and actual synthesis of asparagine from aspartate. Actual asparagine synthesis occurred at one-thousandth the rate of the other two reactions. Optimal conditions for quantitative assay of asparagine synthesis were determined in fetal liver extract, which is a rich source of the enzyme. Demonstrable activity in liver fell 6 days after birth to 20% of the fetal value and decreased slowly thereafter to the low adult value. Adult pancreas was the most active tissue found. The asparagine synthetase of fetal liver extracts was significantly inhibited when combined with adult liver or tumor extracts. The inhibitor fractionated with ammonium sulfate in close association with the asparagine synthetase. Therefore, demonstrable activities of asparagine synthetase in tissue extracts, measured in the presence of this inhibitor, do not necessarily parallel the concentrations of the enzyme present.     

四川短尾鼩肝脏和胰腺的组织解剖学研究

对四川短尾鼩肝脏和胰腺的组织解剖结构进行了研究,结果表明:肝脏分为4叶,它们的肝实质完全分开.肝小叶的分界极不明显,1个肝小叶内的肝细胞大小不一致,靠近中央静脉的肝细胞体积较小,而肝小叶外围的肝细胞体积较大.胰腺的形态松散,无法区分出胰头、胰体和胰尾.胰腺小叶非常明显,大小不等.胰腺的组织结构包括外分泌部和胰岛两部分.     

Predictors of ectopic fat accumulation in liver and pancreas in obese men and women

The aim of the present study was to determine the relationship between body fat distribution, adipocytokines, inflammatory markers, fat intake and ectopic fat content of liver and pancreas in obese men and women. A total of 12 lean subjects (mean age 47.25 ± 14.88 years and mean BMI 22.85 ± 2), 38 obese subjects (18 men and 20 women) with mean age 49.1 ± 13.0 years and mean BMI 34.96 ± 4.21 kg/m2 were studied. Measurements: weight, height, BMI, waist circumference, as well as glucose, insulin, HOMA (homeostasis model assessment of insulin resistance), cholesterol, triglycerides, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, daily energy intake, leptin, and adiponectin. Magnetic resonance was used to evaluate visceral, subcutaneous adipose tissue (SCAT) as well as liver and pancreas lipid content using in-phase and out-of-phase magnetic resonance imaging (MRI) sequence. Obese subjects had significantly higher weight, waist circumference, SCAT, deep SCAT, visceral adipose tissue (VAT), liver and pancreatic lipid content than lean subjects. Obese women had significantly lower VAT, liver and pancreas lipid content regardless of same BMI. In multiple regression analyses, the variance of liver lipid content explained by gender and VAT was 46%. When HOMA was added into a multiple regression, a small increase in the proportion of variance explained was observed. A 59.2% of the variance of pancreas lipid content was explained by gender and VAT. In conclusion, obese men show higher VAT and ectopic fat deposition in liver and pancreas than obese women despite same BMI. Independent of overall adiposity, insulin resistance, adiponectin and fat intake, VAT, measured with MRI, is the main predictor of ectopic fat deposition in both liver and pancreas.     

The formation of radiolabeled N1- and N8-acetylspermidine in various rat organs following [14C]spermidine administration

To detect the in vivo formation of acetylspermidine, three female Sprague-Dawley rats were injected intravenously with 20 muCi of [14C]spermidine. Twenty-four hours after the injection of the radiolabel, the kidneys, liver, lungs, pancreas, small intestine, spleen, stomach and thymus were removed under Halothane anesthesia. High performance liquid chromatography (HPLC) of the pooled radiolabeled extracts from each tissue demonstrated the presence of a 14C-labeled material which co-chromatographed with an acetylspermidine standard. Thin layer chromatography (TLC) of the HPLC eluent demonstrated the presence of both radiolabeled N1- and N8-acetylspermidine in the tissues. Concentrations of labeled acetylspermidine ranged from 0.27 to 1.9% of the total tissue radiolabel. The N1-to N8-acetylspermidine ratio in tissues ranged from approx. 5 to 1 in the thymus to 1.5 to 1 in the liver.     

Interplay between Wnt2 and Wnt2bb controls multiple steps of early foregut-derived organ development

The vertebrate liver, pancreas and lung arise in close proximity from the multipotent foregut endoderm. Tissue-explant experiments uncovered instructive signals emanating from the neighbouring lateral plate mesoderm, directing the endoderm towards specific organ fates. This suggested that an intricate network of signals is required to control the specification and differentiation of each organ. Here, we show that sequential functions of Wnt2bb and Wnt2 control liver specification and proliferation in zebrafish. Their combined specific activities are essential for liver specification, as their loss of function causes liver agenesis. Conversely, excess wnt2bb or wnt2 induces ectopic liver tissue at the expense of pancreatic and anterior intestinal tissues, revealing the competence of intestinal endoderm to respond to hepatogenic signals. Epistasis experiments revealed that the receptor frizzled homolog 5 (fzd5) mediates part of the broader hepatic competence of the alimentary canal. fzd5 is required for early liver formation and interacts genetically with wnt2 as well as wnt2bb. In addition, lack of both ligands causes agenesis of the swim bladder, the structural homolog of the mammalian lung. Thus, tightly regulated spatiotemporal expression of wnt2bb, wnt2 and fzd5 is central to coordinating early liver, pancreas and swim bladder development from a multipotent foregut endoderm.     

Combined activities of hedgehog signaling inhibitors regulate pancreas development

Hedgehog signaling is known to regulate tissue morphogenesis and cell differentiation in a dose-dependent manner. Loss of Indian hedgehog (Ihh) results in reduction in pancreas size, indicating a requirement for hedgehog signaling during pancreas development. By contrast, ectopic expression of sonic hedgehog (Shh) inhibits pancreatic marker expression and results in transformation of pancreatic mesenchyme into duodenal mesoderm. These observations suggest that hedgehog signaling activity has to be regulated tightly to ensure proper pancreas development. We have analyzed the function of two hedgehog inhibitors, Hhip and patched 1 (Ptch), during pancreas formation. Our results indicated that loss of Hhip results in increased hedgehog signaling within the pancreas anlage. Pancreas morphogenesis, islet formation and endocrine cell proliferation is impaired in Hhip mutant embryos. Additional loss of one Ptch allele in Hhip-/-Ptch+/- embryos further impairs pancreatic growth and endodermal cell differentiation. These results demonstrate combined requirements for Hhip and Ptch during pancreas development and point to a dose-dependent response to hedgehog signaling within pancreatic tissue. Reduction of Fgf10 expression in Hhip homozygous mutants suggests that at least some of the observed phenotypes result from hedgehog-mediated inhibition of Fgf signaling at early stages.     

Functional,persistent, and extended liver to pancreas transdifferentiation

Pancreatic and duodenal homeobox gene-1 (PDX-1) regulates pancreas development during embryogenesis, whereas in the adult it controls beta-cell function. Here we analyze whether PDX-1 functions as a pancreatic differentiation factor and a bona fide master regulator when ectopically expressed in mature fully differentiated liver in vivo. By ectopic and transient PDX-1 expression in liver in vivo, using the first generation recombinant adenoviruses, we demonstrate that PDX-1 induces in liver a wide repertoire of both exocrine and endocrine pancreatic gene expression. Moreover, PDX-1 induces its own expression (auto-induction), which in turn may explain the long lasting nature of the "liver to pancreas" transdifferentiation. Insulin as well glucagon-producing cells are mainly located in the proximity of hepatic central veins, possibly allowing direct hormone release into the bloodstream, without affecting normal hepatic function. Importantly, we demonstrate that hepatic insulin production triggered by Ad-CMV-PDX-1 recombinant adenovirus administration is functional and prevents streptozotocin-induced hyperglycemia in Balb/c mice even 8 months after the initial treatment. We conclude that PDX-1 plays an important instructive role in pancreas differentiation, not only from primitive gut endoderm but also from mature liver. Transconversion of liver to pancreas may serve as a novel approach for generating endocrine-pancreatic tissue that can replace malfunctioning beta-cells in diabetics.     

Hedgehog signaling regulates expansion of pancreatic epithelial cells

Embryonic Hedgehog signaling is essential for proper tissue morphogenesis and organ formation along the developing gastrointestinal tract. Hedgehog ligands are expressed throughout the endodermal epithelium at early embryonic stages but excluded from the region that will form the pancreas. Ectopic activation of Hedgehog signaling at the onset of pancreas development has been shown to inhibit organ morphogenesis. In contrast, Hedgehog signaling components are found within pancreatic tissue during subsequent stages of development as well as in the mature organ, indicating that a certain level of pathway activation is required for normal organ development and function. Here, we ectopically activate the Hedgehog pathway midway through pancreas development via expression of either Sonic (Shh) or Indian Hedgehog (Ihh) under control of the human Pax4-promoter. Similar pancreatic defects are observed in both Pax4-Shh and Pax4-Ihh transgenic lines, suggesting that regulation of the overall level of Hedgehog activity is critical for proper pancreas development. We also show that Hedgehog signaling controls mesenchymal vs. epithelial tissue differentiation and that pathway activation impairs formation of epithelial progenitors. Thus, tight control of Hedgehog pathway activity throughout embryonic development ensures proper pancreas organogenesis.     

封闭群草原兔尾鼠肝脏和胰腺的组织学观察

首次对封闭群草原兔尾鼠的肝脏、胰腺进行了组织学观察,结果表明：1．草原兔尾鼠的肝脏纤维组织极少,肝小叶间界限不明显;部分中央静脉周围可见少量毛细胆管;门管区较少,分布不均匀,其静脉形状不规则、腔大,胆管及动脉则较小。2．胰腺分叶清晰,腺泡细胞较大,胞浆多呈嗜酸染色;小叶中部腺泡着色较深,外侧腺泡着色较浅;胰岛大小不等,细胞排列呈不规则索状,光镜下未见特殊改变。