cyclin-d1 and Liver-Diseases

Glia maturation factor-β (GMFB) is a bona fide member of the actin depolymerizing factor homology family. Recently, emerging evidence suggested its implication in liver diseases, but data on its role in liver remain limited.. Assessment of GMFB in liver histology, impact on liver regeneration and hepatocyte proliferation, and the underlying molecular pathways were conducted using mouse models with acute liver injury.. GMFB is widely distributed in normal liver. Its expression increases within 24 hours after partial hepatectomy (PHx). Adult Gmfb knockout mice and wild-type littermates are similar in gross appearance, body weight, liver function, and histology. However, compared with wild-type control, Gmfb knockout mice post-PHx develop more serious liver damage and steatosis and have delayed liver regeneration; the dominant change in liver transcriptome at 24 hours after PHx is the significantly suppressed acute inflammation pathways; the top down-regulated gene sets relate to interleukin (IL)6/Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling. Another mouse model intoxicated with carbon tetrachloride replicated these findings. Furthermore, Gmfb knockout and wild-type groups have the similar numbers of Kupffer cells, but Gmfb knockout Kupffer cells once stimulated produce less IL6, tumor necrosis factor, and IL1β. In hepatocytes treated with IL6, GMFB associates positively with cell proliferation and STAT3/cyclin D1 activation, but without any direct interaction with STAT3. In Gmfb knockout hepatocytes, cytoskeleton-related gene expression was changed significantly, with an abnormal-appearing morphology of actin networks. In hepatocyte modeling, actin-filament turnover, STAT3 activation, and metabolite excretion show a strong reliance on the status of actin-filament organization.. GMFB plays a significant role in liver regeneration by promoting acute inflammatory response in Kupffer cells and by intracellularly coordinating the responsive hepatocyte proliferation.

Topics: Actins; Animals; Carbon Tetrachloride; Cyclin D1; Destrin; Glia Maturation Factor; Interleukin-6; Janus Kinases; Liver Diseases; Liver Regeneration; Mice; Mice, Knockout; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

Liver ischemia-reperfusion injury (IRI) is an inevitable process during liver transplantation, hemorrhagic shock, resection, and other liver surgeries. It is an important cause of postoperative liver dysfunction and increased medical costs. The protective effects of the vagus nerve on hepatic IRI have been reported, but the underlying mechanism has not been fully understood. We established a hepatic vagotomy (Hv) mouse model to study the effect of the vagus on liver IRI and to explore the underlying mechanism. Liver IRI was more serious in mice with Hv, which showed higher serum ALT and AST activities and histopathological changes. Further experiments confirmed that Hv significantly downregulated the expression of IL-22 protein and mRNA in the liver, blocking the activation of the STAT3 pathway. The STAT3 pathway in the livers of Hv mice was significantly activated, and liver injury was clearly alleviated after treatment with exogenous IL-22 recombinant protein. In conclusion, Hv can aggravate hepatic IRI, and its mechanism may be related to inhibition of IL-22 expression and downregulation of the STAT3 pathway in the liver.

Topics: Animals; Cyclin D1; Disease Models, Animal; Disease Progression; Disease Susceptibility; Gene Expression; Immunohistochemistry; Interleukin-22; Interleukins; Liver Diseases; Male; Mice; Nerve Block; Phosphorylation; Reperfusion Injury; STAT3 Transcription Factor; Vagus Nerve

Inflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5'-methylthioadenosine (MTA) in Mdr2(-/-) mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development.. MTA was administered daily by gavage to wild type and Mdr2(-/-) mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2(-/-) mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts).. MTA treatment reduced hepatomegaly and liver injury. α-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGFβ2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts.. Oral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis.

Topics: Adenosine; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Cyclin D1; Cytokines; Disease Progression; Fibroblasts; Fibrosis; Inflammation; Liver; Liver Diseases; Mice; Mice, Transgenic; Proto-Oncogene Proteins c-jun; Thionucleosides

Liver injury initiated by non-lethal doses of CCl(4) and thioacetamide (TA) progresses to hepatic failure and death of type 2 diabetic (DB) rats due to failed advance of liver cells from G(0)/G(1) to S-phase and inhibited tissue repair. Objective of the present study was to investigate cellular signaling mechanisms of failed cell division in DB rats upon hepatotoxicant challenge. In CCl(4)-treated non-diabetic (non-DB) rats, increased IL-6 levels, sustained activation of extracellular regulated kinases 1/2 (ERK1/2) MAPK, and sustained phosphorylation of retinoblastoma protein (p-pRB) via cyclin D1/cyclin-dependent kinase (cdk) 4 and cyclin D1/cdk6 complexes stimulated G(0)/G(1) to S-phase transition of liver cells. In contrast to the non-DB rats, CCl(4) administration led to lower plasma IL-6, decreased ERK1/2 activation, lower cyclin D1, and cdk 4/6 expression resulting in decreased p-pRB and inhibition of liver cell division in the DB rats. Furthermore, higher TGFbeta1 expression and p21 activation may also contribute to decreased p-pRB in DB rats compared to non-DB rats. Similarly, after TA administration to DB rats, down-regulation of cyclin D1 and p-pRB leads to markedly decreased advance of liver cells from G(0)/G(1) to S-phase and tissue repair compared to the non-DB rats. Hepatic ATP levels did not differ between the DB and non-DB rats obviating its role in failed tissue repair in the DB rats. In conclusion, decreased p-pRB may contribute to blocked advance of cells from G(0)/G(1) to S-phase and failed cell division in DB rats exposed to CCl(4) or TA, leading to progression of liver injury and hepatic failure.

Topics: Adenosine Triphosphate; Animals; Carbon Tetrachloride Poisoning; Cell Cycle; Chemical and Drug Induced Liver Injury; Cyclin D1; Cyclin-Dependent Kinases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Immunoblotting; Interleukin-6; Liver Diseases; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Retinoblastoma Protein; Thioacetamide; Transforming Growth Factor beta1

Eukaryotic cell cycle is regulated by signal transduction pathways mediated by complexes of cyclin dependent kinases (CDKs) and their partner cyclins, or by interaction with CDK inhibitors. Thioacetamide (TA) is a weak hepatocarcinogen causing several types of liver damage in a dose dependent manner and ultimately producing malignant transformation. We investigated alterations of expression of cell cycle regulators in the rat liver, involved in G1 entry and progression during TA administration.. We studied expression patterns of cyclin D1, CDK4, CDK6, p21(CIP1) and p16(INK4a) during daily intraperitoneal injection of low dose TA (50 mg/kg) till 7 day. We used western blot and immunohistochemistry for detection.. Expression of cyclin D1, CDK4, CDK6 and p21(CIP1) increased from 6 hour and peaked at 2, 3 day, then decreased next 2 days, and re-increased at 6 day. Cytoplasmo-nuclear translocation of cyclin D1 and p21(CIP1) was evident within 1 day and prominent at 2 and 7 day. Expression of p16(INK4a) increased immediately after TA treatment and remarkably increased from 3 day and progressed till 7 day, showing cytoplasmic location, suggestive of inactive form. Most of in situ immunoreactions occurred at the centrilobular hepatocytes. Concomitant nuclear translocation of p21(CIP1) and cyclin D1, different with p16(INK4a) suggests that p21(CIP1) might be a transporter for nuclear translocation rather than cell cycle inhibitor.. Daily administration of low dose TA makes cell cycle open and G1 progress, possibly due to cyclin D1, CDK4 and CDK 6, their transporter p21(CIP1), and inactive p16(INK4a), which occur at quiescent hepatocytes, not stem cells.

Topics: Animals; Cell Cycle Proteins; Chemical and Drug Induced Liver Injury; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; G1 Phase; Immunohistochemistry; Liver; Liver Diseases; Male; Rats; Rats, Sprague-Dawley; Thioacetamide

Liver integrity and function are crucial for survival of patients suffering from trauma, operations or infections. Insulin decreased mortality and prevented the incidence of multi organ failure and infection in critically ill patients. The aim of the present study was to determine whether insulin exerts positive effects on hepatic homeostasis and function during endotoxemia.. Endotoxemic rats received either saline or insulin. Hepatic morphology and function was determined by measuring the effect of insulin on liver proteins, enzymes, hepatocyte apoptosis and proliferation including caspases-3 and -9 and Bcl-2. Intrahepatic ATP, glucose and lactate concentration were determined by bioluminescence. To determine possible molecular changes the effect of insulin on hepatic cytokine mRNA and gene profile analysis were assessed.. Insulin significantly improved hepatic protein synthesis by increasing albumin and decreasing c-reactive protein, P<0.05. Insulin attenuated hepatic damage by decreasing AST and ALT, P<0.05. Improved liver morphology was due to decreased hepatocyte apoptosis along with decreased caspase-3 concentration and increased hepatocyte proliferation along with Bcl-2 concentration, P<0.05. Insulin decreased hepatic IL-1beta, IL-6 and MIF mRNA and improved hepatic glucose metabolism and glycolysis, P<0.05. GeneChip analysis revealed an anti-inflammatory effect of insulin.. Insulin improves hepatic integrity, hepatic glucose metabolism and hepatic function by increasing cell survival and attenuating the hepatic inflammatory response in endotoxemic rats.

Topics: Acute-Phase Proteins; Adenosine Triphosphate; Animals; Apoptosis; Blood Glucose; Caspase 3; Caspase 9; Caspases; Cell Division; Cyclin D1; Cytokines; Electrolytes; Endotoxemia; Hepatocytes; Hypoglycemic Agents; Insulin; Lactic Acid; Lipopolysaccharides; Liver; Liver Diseases; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis

Exposure of pregnant mice to inorganic arsenic induces a spectrum of tumors, including hepatocellular carcinoma (HCC), in their adult offspring similar to that induced by exposing adult mice to estrogenic compounds. To investigate whether arsenic exposure in utero causes altered estrogen signaling, we examined expression of estrogen receptor-alpha (ER-alpha), cyclin D1 (an estrogen-responsive hepatic oncogene), and several cytochrome P450 genes (with sexually dimorphic liver expression patterns) in livers from adult male mice with in utero arsenic-induced HCC.. Quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate gene expression in livers of adult male mice that had (i.e., exposed mice; n = 8) or had not (i.e., control mice; n = 5) been exposed to arsenic in utero. DNA methylation status of portions of the ER-alpha and cyclin D1 gene promoters in liver tissue was measured using methylation-specific polymerase chain reaction. Statistical tests were two-sided.. ER-alpha mRNA levels were 3.1-fold (95% confidence interval [CI] = 2.0-fold to 4.3-fold) higher in livers of exposed mice than in those of control mice, and cyclin D1 levels were 3.0-fold (95% CI = 1.7-fold to 4.3-fold) higher. Exposed mice showed a feminized expression pattern of several cytochrome P450 genes, expressing the female-dominant CYP2A4 (P =.017 versus control) and CYP2B9 (P<.001) genes at 8.7 and 10.5 times, respectively, the level in control mice and expressing the male-dominant CYP7B1 at approximately one-fourth the level in control mice(P =.0012). Exposed mice exhibited reduced (by approximately 90%) methylation of the ER-alpha gene promoter in liver DNA as compared with control mice; the cyclin D1 gene promoter was not methylated in either exposed or control mice.. Altered estrogen signaling may play a role in induction of HCC by arsenic exposure in utero. Specifically, overexpression of ER-alpha, potentially through promoter region hypomethylation, in livers of such mice may be linked to the hepatocarcinogenicity of arsenic.

Topics: Animals; Arsenicals; Aryl Hydrocarbon Hydroxylases; Carcinogens; Chemical and Drug Induced Liver Injury; Cyclin D1; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Cytochrome P450 Family 7; DNA Methylation; Environmental Exposure; Estrogen Receptor alpha; Estrogens; Fetus; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Liver; Liver Diseases; Liver Neoplasms, Experimental; Male; Mice; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Steroid Hydroxylases

In spite of the importance of periodic screening for hepatocellular carcinoma (HCC) by ultrasonography (US) in patients with underlying liver disease, the clinicopathological characteristics of hyperechoic nodules have not been clearly evaluated. The aim of this study was to characterize the pathological and proliferating features of small hyperechoic nodules. Tissue specimens of 55 hyperechoic and 107 hypoechoic nodules less than 20 mm in diameter in patients with chronic liver disease were obtained by echo-guided needle biopsy and examined histopathologically. Of these, 42 (76%) hyperechoic and 56 (52%) hypoechoic nodules were diagnosed as HCC, and 82% of hyperechoic HCCs contained fatty change and/or clear cell change. In addition, immunohistochemical staining using cyclin D1, p53, and Ki-67 was examined. A high-level expression of cyclin D1 was found in only 5% of hyperechoic HCCs, in contrast to 38% of hypoechoic HCCs (P <.02). The labeling index of Ki-67 in hyperechoic HCCs was lower than in hypoechoic HCCs (4.2% vs. 8.9%; P <.003). However, there was no difference on p53 staining between them. Retrospective follow-up study revealed that hyperechoic nodules showed slow growth (doubling time, median: 1,403 days) initially, and came to show rapid growth (doubling time, median: 56 days). From these results, small hyperechoic nodules in chronic liver diseases are worth notice as candidates for well-differentiated HCC with low cyclin D1 and Ki-67 expression.

Topics: Adult; Aged; Aged, 80 and over; Biopsy, Needle; Carcinoma, Hepatocellular; Cell Nucleus; Cyclin D1; Female; Humans; Ki-67 Antigen; Liver; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Tumor Suppressor Protein p53; Ultrasonography