Sex-dependent pituitary growth hormone (GH) secretory profiles-pulsatile in males and persistent in females-regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, ...imparting sex differences in hepatic drug/lipid metabolism and disease risk. Here, we examine transcriptional and epigenetic changes induced by continuous GH infusion (cGH) in male mice, which rapidly feminizes the temporal profile of liver STAT5 activity. cGH repressed 86% of male-biased genes and induced 68% of female-biased genes within 4 days; however, several highly female-specific genes showed weak or no feminization, even after 14 days of cGH treatment. Female-biased genes already in an active chromatin state in male liver generally showed early cGH responses; genes in an inactive chromatin state often responded late. Early cGH-responsive genes included those encoding two GH/STAT5-regulated transcriptional repressors: male-biased BCL6, which was repressed, and female-specific CUX2, which was induced. Male-biased genes activated by STAT5 and/or repressed by CUX2 were enriched for early cGH repression. Female-biased BCL6 targets were enriched for early cGH derepression. Changes in sex-specific chromatin accessibility and histone modifications accompanied these cGH-induced sex-biased gene expression changes. Thus, the temporal, sex-biased gene responses to persistent GH stimulation are dictated by GH/STAT5-regulated transcription factors arranged in a hierarchical network and by the dynamics of changes in sex-biased epigenetic states.
Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. ...This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.
Management of Alcoholic Liver Disease: An Update Kershenobich, David; Corona, Dana Lau; Kershenovich, Ruben ...
Alcoholism, clinical and experimental research,
20/May , Letnik:
35, Številka:
5
Journal Article, Conference Proceeding
Recenzirano
Treatment of alcoholic liver disease is for the most part based on the stage of the disease and the pathogenic event that is being targeted. The primary treatment modalities that are considered in ...the treatment of alcoholic liver disease include abstinence, agents that suppress inflammation, anticytokine therapy, nutritional support, modifiers of alcohol metabolism, anti‐oxidants, and inhibitors of hepatic fibrosis. Future therapeutic options include exploration of new pathways such as the patatin‐like phospholipase domain containing 3 protein (PNPLA‐3).
Senescent cells occur in adults with cirrhotic livers independent of the etiology.
Investigate the presence rate of cellular senescence and expression of cell cycle check points in livers from ...children with end stage disease.
Livers of five children aged three years or less undergoing liver transplantation due to tyrosinemia (n = 1), biliary atresia (n = 2), or fulminant hepatitis (n = 2) were analyzed for senescence associated beta-galactosidase (SA-betagal) activity and p16INK4a, p21cip1 and p53. All livers displayed positive cellular staining for SA-betagal in the canals of Hering and interlobular biliary ducts. In the presence of cirrhosis (3/5 cases) SA-betagal was found at the cholangioles and hepatocytes surrounding the regenerative nodules. Children with fulminant hepatic failure without cirrhosis had significant ductular transformation with intense SA-betagal activity. No SA-betagal activity was evident in the fibrous septa. Staining for p53 had a similar distribution to that observed for SA-betagal. Staining for p16(INK4a) and p21(cip1) was positive in the explanted liver of the patient with tyrosinemia, in the hepatocytes, the canals of Hering, cholangioles and interlobular bile ducts. In the livers with fulminant hepatitis, p21(cip1) staining occurred in the areas of ductular transformation and in the interlobular bile ducts.
Cellular senescence in livers of children with end stage disease is associated with damage rather than corresponding to an age dependent phenomenon. Further studies are needed to support the hypothesis that these senescence markers correlate with disease progression.
Abstract
Sex differences in pituitary growth hormone (GH) secretion (pulsatile in males vs near continuous/persistent in females) impart sex-dependent expression to hundreds of genes in adult mouse ...liver. Signal transducer and activator of transcription (STAT) 5, a GH-activated transcription factor that is essential for liver sexual dimorphism, is dynamically activated in direct response to each male plasma GH pulse. However, the impact of GH-induced STAT5 pulses on liver chromatin accessibility and downstream transcriptional events is unknown. In this study, we investigated the impact of a single pulse of GH given to hypophysectomized mice on local liver chromatin accessibility (DNase hypersensitive site analysis), transcription rates (heterogeneous nuclear RNA analysis), and gene expression (quantitative polymerase chain reaction and RNA sequencing) determined 30, 90, or 240 minutes later. The STAT5-dependent but sex-independent early GH response genes Igf1 and Cish showed rapid, GH pulse–induced increases in chromatin accessibility and gene transcription, reversing the effects of hypophysectomy. Rapid increases in liver chromatin accessibility and transcriptional activity were also induced in hypophysectomized male mice for some (Ces2b, Ugt2b38) but not for other liver STAT5-dependent male-biased genes (Cyp7b1). Moreover, in pituitary-intact male mice, Igf1, Cish, Ces2b, and Ugt2b38 all showed remarkable cycles of chromatin opening and closing, as well as associated cycles of induced gene transcription, which closely followed each endogenous pulse of liver STAT5 activity. Thus, the endogenous rhythms of male plasma GH pulsation dynamically open and then close liver chromatin at discrete, localized regulatory sites in temporal association with transcriptional activation of Igf1, Cish, and a subset of STAT5-dependent male-biased genes.
Igf1, Cish, and a subset of male-biased liver genes undergo rapid pulsatile increases in chromatin accessibility and gene transcription with each male plasma GH pulse–induced cycle of STAT5 activation.
STAT5 is an essential transcriptional regulator of the sex-biased actions of GH in the liver. Delivery of constitutively active STAT5 (STAT5CA) to male mouse liver using an engineered ...adeno-associated virus with high tropism for the liver is shown to induce widespread feminization of the liver, with extensive induction of female-biased genes and repression of male-biased genes, largely mimicking results obtained when male mice are given GH as a continuous infusion. Many of the STAT5CA-responding genes were associated with nearby (< 50 kb) sites of STAT5 binding to liver chromatin, supporting the proposed direct role of persistently active STAT5 in continuous GH-induced liver feminization. The feminizing effects of STAT5CA were dose-dependent; moreover, at higher levels, STAT5CA overexpression resulted in some histopathology, including hepatocyte hyperplasia, and increased karyomegaly and multinuclear hepatocytes. These findings establish that the persistent activation of STAT5 by GH that characterizes female liver is by itself sufficient to account for the sex-dependent expression of a majority of hepatic sex-biased genes. Moreover, histological changes seen when STAT5CA is overexpressed highlight the importance of carefully evaluating such effects before considering STAT5 derivatives for therapeutic use in treating liver disease.
AIM： To assess the usefulness of FibroTest to forecast scores by constructing decision trees in patients with chronic hepatitis C.
METHODS： We used the C4.5 classification algorithm to construct ...decision trees with data from 261 patients with chronic hepatitis C without a liver biopsy. The FibroTest attributes of age, gender, bilirubin, apolipoprotein, haptoglobin, α2 macroglobulin, and γ-glutamyl transpeptidase were used as predictors, and the FibroTest score as the target. For testing, a 10-fold cross validation was used.
RESULTS： The overall classification error was 14.9% （accuracy 85.1%）. FibroTest＇s cases with true scores of FO and F4 were classified with very high accuracy （18/20 for FO, 9/9 for FO-1 and 92/96 for F4） and the largest confusion centered on F3. The algorithm produced a set of compound rules out of the ten classification trees and was used to classify the 261 patients. The rules for the classification of patients in FO and F4 were effective in more than 75% of the cases in which they were tested.
CONCLUSION： The recognition of clinical subgroups should help to enhance our ability to assess differences in fibrosis scores in clinical studies and improve our understanding of fibrosis progression,
The sex-dependent pituitary growth hormone (GH) secretory profiles, pulsatile in males and persistent in females, regulate sex-biased expression of hundreds of genes in mammalian liver, contributing ...to sex differences in hepatic metabolism and disease. The sex-biased GH actions in the liver are mediated by STAT5b and enhanced by a network of transcription factors including the male-biased BCL6 and the female-specific CUX2, acting in the context of sex-biased chromatin states. First, the transcriptional and epigenomic changes induced by continuous-GH infusion (cGH) in male mice, which rapidly feminizes the temporal profile of liver STAT5 activity, were examined. RNA-seq analysis determined that cGH repressed the majority of male-biased genes and induced most female-biased genes within 4-days; however, several highly female-specific genes showed partial feminization. Female-biased genes already in an active chromatin state in male liver were induced early; genes in an inactive chromatin state often responded late. Early cGH-responsive genes included Cux2 and Bcl6 and their targets. DNase-seq and ChIP-seq were used to identify changes in sex-specific chromatin accessibility and histone modifications accompanying these cGH-induced gene expression changes. H3-K27me3 is a key sex-biased repressive mark found preferentially at highly female-biased genes in male mouse liver. Consistently, induction of female-biased genes by cGH was associated with loss of H3-K27me3 at their gene bodies. H3K27 methylation is catalyzed by Polycomb Repressive Complex-2 (PRC2) through its homologous catalytic subunits EZH1 and EZH2. An Ezh1-knockout mouse model with a hepatocyte-specific knockout of Ezh2 (DKO) was used to further investigate the role of H3-K27me3 in repressing sex-biased genes in mouse liver. Loss of Ezh1/Ezh2 led to a significant decrease in sex-specific gene expression, with many female-biased genes induced and male-biased genes repressed. These gene responses were more extensive in male than female liver, as was the loss of H3K27me3 sites and the reciprocal increases in active histone marks. There was substantial up-regulation of liver cancer and liver fibrosis-related genes in male and female DKO-mouse liver, with a subset of genes preferentially up-regulated in females. Thus, GH regulated sex-biased liver physiology is dictated by transcription factors arranged in a hierarchical network and by dynamic sex-biased epigenetic states.
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