Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In carbon tetrachloride-induced liver cirrhosis, diminution of hepatic endothelial nitric oxide synthase (eNOS) activity may contribute to impaired hepatic vasodilation and portal hypertension. The mechanisms responsible for these events remain unknown; however, a role for the NOS-associated proteins caveolin and calmodulin has been postulated. The purpose of this study is to characterize the expression and cellular localization of the NOS inhibitory protein caveolin-1 in normal rat liver and to then examine the role of caveolin in conjunction with calmodulin in regulation of NOS activity in cholestatic portal hypertension. In normal liver, caveolin protein is expressed preferentially in nonparenchymal cells compared with hepatocytes as assessed by Western blot analysis of isolated cell preparations. Additionally, within the nonparenchymal cell populations, caveolin expression is detected within both liver endothelial cells and hepatic stellate cells. Next, studies were performed 4 wk after bile duct ligation (BDL), a model of portal hypertension characterized by prominent cholestasis, as evidenced by a significant increase in serum cholesterol in BDL animals. After BDL, caveolin protein levels from detergent-soluble liver lysates are significantly increased as assessed by Western blot analysis. Immunoperoxidase staining demonstrates that this increase is most prominent within sinusoids and venules. Additionally, caveolin-1 upregulation is associated with a significant reduction in NOS catalytic activity in BDL liver lysates, an event that is corrected with provision of excess calmodulin, a protein that competitively binds eNOS from caveolin. We conclude that, in cholestatic portal hypertension, caveolin may negatively regulate NOS activity in a manner that is reversible by excess calmodulin.
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PMID:Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. 1135 14

BACKGROUND: In cirrhotic livers, the balance of vasoactive substances is in favour of vasoconstrictors with relatively insufficient nitric oxide. Endothelial dysfunction has been documented in cirrhotic rat livers leading to a lower activity of endothelial nitric oxide synthase but this might not be sufficient to explain the low nitric oxide presence. We compared the amount of all nitric oxide synthase isoforms and other factors that influence nitric oxide bioavailability in livers of two portal hypertensive rat models: prehepatic portal hypertension and carbon tetrachloride induced cirrhosis, in comparison with healthy controls. RESULTS: Endothelial nitric oxide synthase was the solely detected isoform by Western blotting in all livers. In cirrhotic livers, the amount of endothelial nitric oxide synthase protein was lower than in healthy controls, although an overlap existed. Levels of caveolin-1 messenger RNA were within the normal range but endothelin-1 messenger RNA levels were significantly higher in cirrhotic livers (p < 0.05). A markedly lower superoxide dismutase activity was observed in cirrhotic livers as compared to healthy controls (p < 0.05). CONCLUSIONS: In contrast to prehepatic portal hypertension, cirrhotic livers had decreased endothelial nitric oxide synthase protein and enhanced endothelin-1 messenger RNA amount. We hypothesise that a vasodilator/vasoconstrictor imbalance may be further aggravated by the reduced activity of superoxide dismutase. Decreased activity allows enhanced superoxide action, which may lead to breakdown of nitric oxide in liver sinusoids.
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PMID:Low NO bioavailability in CCl4 cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: A comparison of two portal hypertensive rat models with healthy controls. 1257 97

Hepatocellular carcinoma is a common malignancy causing significant morbidity and mortality worldwide. In this study we use expression microarray technology to identify novel genes that consistently displayed altered expression levels in the earliest identifiable precursors to hepatocellular carcinoma, dysplastic and macroregenerative nodules. The gene expression profiles from nine patients with end-stage hepatitis C cirrhosis that contained a combined 11 dysplastic or macroregenerative nodules were compared to the patient's matched cirrhotic liver tissue. A total of 53 genes were consistently dysregulated in the patient liver specimens. Six of seven genes were validated by quantitative real-time reverse transcriptase-polymerase chain reaction, or by immunohistochemical studies performed on an independent set of lesions. The novel genes, including caveolin-1, semaphorin E, and FMS-like tyrosine kinase 3 ligand, have putative roles in carcinogenesis but have not been reported in hepatocellular carcinogenesis. Microarray expression analysis of dysplastic and macroregenerative liver nodules provide insight into the earliest changes in hepatocellular carcinogenesis.
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PMID:cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis. 1259 31

Macroregenerative and dysplastic nodules (MDNs) are hepatocellular carcinoma (HCC) precursor lesions and exhibit distinct vascular profiles relative to adjacent cirrhotic liver. Recent microarray analysis of MDN identified aberrant expression of caveolin-1 and thrombospondin-1, genes suspected to play a role in tumorigenesis at other sites. We used immunohistochemistry to localize caveolin and thrombospondin expression in 14 MDNs from livers with hepatitis C cirrhosis and in tissue arrays that included samples of MDNs, HCC, and nonneoplastic liver. Hepatocytes were uniformly negative for caveolin. Sinusoidal endothelial cells exhibited increased caveolin expression in MDNs relative to adjacent cirrhotic liver in most (28 of 36, 78%) MDNs evaluated. However, few HCCs showed increased caveolin expression as compared with nonneoplastic liver (5 of 19, 26%). Unpaired arteries showed strong positive endothelial cell staining. Thrombospondin staining was weak or negative in hepatocytes in nearly all (77 of 92, 84%) MDNs and in 46 of 49 HCCs evaluated (94%). Sinusoidal endothelial cells were negative for thrombos pondin, but hepatic arteries and MDNs showed positive mural staining; portal veins were positive both in vessel walls and in endothelial cells. The altered expression profiles of these genes identified in microarray analysis are not likely related directly to malignant transformation of hepatocytes but rather to an alteration in the vascular supply to these lesions. The results illustrate the critical role of histologic techniques in interpretation of microarray data.
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PMID:Caveolin and thrombospondin expression during hepatocellular carcinogenesis. 1510 98

Most vascular endothelial cells are continuously exposed to shear stress in vivo. Caveolae are omega-shaped membrane invaginations in endothelial cells (ECs) and are enriched in cholesterol, caveolins, and signaling molecules. This study was designed to elucidate the ultrastructural localization and change in caveolin-1 expression within human liver sinusoidal endothelial cells (LSECs) during the progression of cirrhosis caused by hepatitis C, using tissue sections prepared via perfusion-fixation. Normal control liver specimens and hepatitis C-related Child-Pugh A and C cirrhotic liver specimens were studied. Caveolin-1 in the liver sinusoids was examined via immunohistochemistry, Western blotting, and immunoelectron microscopy. In control liver tissue, caveolin-1 was localized on caveolae mainly in arterial and portal endothelial cells of the portal tract and was also found on vesicles and some fenestrae in LSECs around the central vein. In cirrhotic liver tissue, aberrant caveolin-1 expression was observed on caveolae-like structures in LSECs. Caveolin-1 was especially overexpressed in late-stage cirrhosis. This study demonstrates that caveolin-1 is strongly expressed within caveolae-like structures and associated vesicles within LSECs of the hepatitis C-related cirrhotic liver. These findings suggest a direct association of caveolin-1 in the process of differentiation of LSECs in cirrhosis-mediated capillarization.
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PMID:Relation between ultrastructural localization, changes in caveolin-1, and capillarization of liver sinusoidal endothelial cells in human hepatitis C-related cirrhotic liver. 2311 35

Sinusoidal endothelial cells (SEC) and hepatic stellate cells (HSC) are closely associated specialized vascular cells residing in the hepatic sinusoid. These cells have been shown to play important roles in many different pathophysiologic processes, in particular in liver fibrosis/cirrhosis and portal hypertension. Caveolin-1 functions as a scaffolding protein, and has a variety of functions including in many disease states, such as liver cirrhosis. Although previous studies have shown that in the injured rat liver, caveolin-1 is upregulated, the precise cells in which remains unclear. Therefore, the purpose of this study was to clarify the cell type (or types) in which caveolin-1 is expressed in normal and injured rat liver. We have utilized both detailed immunohistochemical labeling with cell specific markers as well as cell isolation techniques (isolating sinusoidal endothelial cells, HSCs, and hepatocytes) in normal and injured (bile duct ligation) rat liver. We show here that in the normal liver caveolin-1 is expressed predominantly in HSCs and SECs but after liver injury there is upregulation of caveolin-1 in HSCs, but not in SECs. These data have functional implications for the cells in which caveolin-1 is regulated.
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PMID:Caveolin-1 is upregulated in hepatic stellate cells but not sinusoidal endothelial cells after liver injury. 2684 75

Hepatocellular carcinoma (HCC) occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Toll-like receptors (TLRs) play an important role in innate immune responses and TLR signaling has been associated with various chronic liver diseases. Lipid rafts provide the necessary microenvironment for certain specialized signaling events to take place, such as the innate immune recognition. The purpose of this study was to determine the pattern of TLR7 expression in HCC, how to recruit TLR7 into lipid rafts responded to ligands and whether targeting TLR7 might have beneficial effects. The study group was comprised of 130 human liver tissues: 23 chronic hepatitis B (CHB), 18 liver cirrhosis (LC), 68 HCC and 21 normal livers. The expression of TLR7 was evaluated using immunohistochemistry, western blotting, and flow cytometry. Proliferation and migration of human HepG2 cells were studied following stimulation of TLR7 using the agonist gardiquimod and inhibition with a specific antagonist 20S-protopanaxadiol (aPPD). The activation of lipid raft-associated TLR7 signaling was measured using western blotting, double immunohistochemistry and immunoprecipitation in liver tissues and HepG2 cells. TLR7 expression was up-regulated in human HCC tissues and hepatoma cell line. Proliferation and migration of HepG2 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 inhibition using aPPD significantly reduced HepG2 cell migration in vitro. The lipid raft protein caveolin-1 and flotillin-1 were involved with enhanced TLR7 signaling in HCC.
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PMID:Lipid rafts promote liver cancer cell proliferation and migration by up-regulation of TLR7 expression. 2758 80

Caveolin-1 (CAV1), the structural protein of caveolae in the plasma membrane, has emerged as a regulator of liver function. CAV1 modulates several molecular pathways leading to the regulation of hepatic lipid accumulation, lipid and glucose metabolism, mitochondrial biology, and hepatocyte proliferation. CAV1 thus plays a crucial role in maintaining hepatic physiology during metabolic adaptation to fasting, liver steatosis, and hepatocyte proliferation associated with liver regeneration. With failure of such processes, CAV1 has been implicated in the modulation of cholestasis, hepatitis, cirrhosis, and hepatocarcinogenesis. This review discusses the latest research in CAV1 biology and related proteins, aiming to guide future endeavors that explore their role in liver physiology and disease.
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PMID:Caveolin-1 Function in Liver Physiology and Disease. 2763 17

Excessive alcohol uptake exerts hepatocellular toxicity, ultimately leading to multiple liver diseases such as steatohepatitis and liver cirrhosis. Here, we aimed to explore the effects of mulberry leaf extract (MLE) and its major components chlorogenic acid (CGA) and neochlorogenic acid (nCGA) on alcoholic steatohepatitis. We determined the composition of MLE using liquid chromatography-mass spectrometric (LC-MS) analysis, which showed that MLE consisted of mainly chlorogenic acid derivatives and other polyphenols. Next, we utilized a high alcohol-fed mouse model and demonstrated that MLE alleviated alcohol-induced hepatocellular disorders, resulting in lowered hepatic injury markers and lipid accumulation. In addition, MLE reduced lipid peroxidation and meanwhile elevated hepatic superoxide dismutase (SOD). Immunohistochemical (IHC) staining revealed that MLE elevated the expression of caveolin-1 but reduced the expressions of epidermal growth factor receptor (EGFR), signal transducer and activator of transcription (STAT), inducible nitric oxide synthase (iNOS) and receptor interacting protein (RIP) 1/3. Major components of MLE, CGA and nCGA, not only exerted a similar biological activity as MLE but also inhibited alcohol-induced pro-apoptotic signals. Involvement of caveolin-1 in MLE, CGA and nCGA was demonstrated by using specific small inhibitory RNA. In conclusion, MLE and its chlorogenic derivatives CGA and nCGA upregulate caveolin-1 expression and diminish EGFR/STAT3/iNOS signalling, which may contribute to lowered hepatic lipid accumulation and peroxidation and inhibited pro-apoptotic cascades.
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PMID:Upregulation of caveolin-1 by mulberry leaf extract and its major components, chlorogenic acid derivatives, attenuates alcoholic steatohepatitis via inhibition of oxidative stress. 2807 52

Autophagy plays important roles in maintaining cellular homeostasis. It uses double- or multiple-membrane vesicles termed autophagosomes to remove protein aggregates and damaged organelles from the cytoplasm for recycling. Hepatitis C virus (HCV) has been shown to induce autophagy to enhance its own replication. Here we describe a procedure that combines membrane flotation and affinity chromatography for the purification of autophagosomes from cells that harbor an HCV subgenomic RNA replicon. The purified autophagosomes had double- or multiple-membrane structures with a diameter ranging from 200 nm to 600 nm. The analysis of proteins associated with HCV-induced autophagosomes by proteomics led to the identification of HCV nonstructural proteins as well as proteins involved in membrane trafficking. Notably, caveolin-1, caveolin-2, and annexin A2, which are proteins associated with lipid rafts, were also identified. The association of lipid rafts with HCV-induced autophagosomes was confirmed by Western blotting, immunofluorescence microscopy, and immunoelectron microscopy. Their association with autophagosomes was also confirmed in HCV-infected cells. The association of lipid rafts with autophagosomes was specific to HCV, as it was not detected in autophagosomes induced by nutrient starvation. Further analysis indicated that the autophagosomes purified from HCV replicon cells could mediate HCV RNA replication in a lipid raft-dependent manner, as the depletion of cholesterol, a major component of lipid rafts, from autophagosomes abolished HCV RNA replication. Our studies thus demonstrated that HCV could specifically induce the association of lipid rafts with autophagosomes for its RNA replication.IMPORTANCE HCV can cause severe liver diseases, including cirrhosis and hepatocellular carcinoma, and is one of the most important human pathogens. Infection with HCV can lead to the reorganization of membrane structures in its host cells, including the induction of autophagosomes. In this study, we developed a procedure to purify HCV-induced autophagosomes and demonstrated that HCV could induce the localization of lipid rafts to autophagosomes to mediate its RNA replication. This finding provided important information for further understanding the life cycle of HCV and its interaction with the host cells.
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PMID:Hepatitis C Virus Induces the Localization of Lipid Rafts to Autophagosomes for Its RNA Replication. 2874 6


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