Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 (MKP1) in sexual dimorphism and susceptibility to alcohol induced liver injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE250473 | GEO | 2024/02/26
REPOSITORIES: GEO
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Project description:Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 (MKP1) in sexual dimorphism and susceptibility to alcohol induced liver injury
| PRJNA1054127 | ENA
Project description:Humanized liver mouse models are crucial tools in liver research, specifically in the fields of liver cell biology, viral hepatitis and drug metabolism. The livers of these humanized mouse models are repopulated by 3-dimensional islands of fully functional primary human hepatocytes (PHH), which are notoriously difficult to maintain in vitro. As low efficiency and high cost hamper widespread use, optimization is of great importance. In the present study, we analyzed experimental factors associated with Hepatitis E virus (HEV) infection and PHH engraftment in 2 xenograft systems on a Nod-SCID-IL2Ry-/- background: the alb-urokinase plasminogen activator mouse model (uPA-NOG, n=399); and the alb-HSV thymidine kinase model (TK-NOG, n = 198). In a first analysis, HEV fecal shedding in liver humanized uPA-NOG and TK-NOG mice with comparable human albumin levels was found to be similar irrespective of the mouse genetic background. In a second analysis, sex, mouse age at transplantation and hepatocyte donor were the most determinant factors for xenograft success in both models. The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.
| S-EPMC8114754 | biostudies-literature
Project description:There is a growing interest in understanding how lifestyle choices and social factors affect life expectancy, healthspan, and the onset of chronic age-related diseases, including cancer. Although alcohol is a known carcinogen that accounts for roughly one-third of primary liver cancer cases worldwide, it is not yet known if chronic alcohol consumption by an individual’s parents heritably influences their predisposition to developing liver cancer. Here, we employed our established multiplex mouse model to compare sensitivities of the male offspring of maternal, paternal, and dual-parental alcohol exposures to the potent hepatocellular carcinoma inducer, Diethylnitrosamine (DEN), and determine their predisposition for tumor formation and growth. Our experiments reveal that chronic parental alcohol consumption programs a pro-tumor environment in the liver. This increased cancer susceptibility correlates with increased steatosis, hepatic fibrosis, inflammation, and oxidative stress. Interestingly, some of these changes display accumulative effects and are more pronounced when both parents are exposed to alcohol.
2024-08-05 | GSE273675 | GEO
Project description:Alcoholic liver disease occurs due to chronic, heavy drinking and is driven both by metabolic alterations and immune cell activation. Women are at a higher risk than men for developing alcohol induced liver injury and this dimorphism is reflected in animal models of alcoholic liver disease. The importance of adipose tissue in alcoholic liver disease is emerging. Chronic alcohol consumption causes adipose tissue inflammation, which can influence liver injury. Sex differences in body fat composition are well known. However, it is still unclear if alcohol-induced adipose tissue inflammation occurs in a sex-dependent manner. Here we have employed the clinically relevant NIAAA model of chronic-binge alcohol consumption to investigate this sexual dimorphism. We report that female mice have greater liver injury than male mice despite lower alcohol consumption. Chronic-binge alcohol induces adipose tissue inflammation in vivo in female mice, which is illustrated by increased expression of TNF?, IL-6, and CCL2, compared to only IL-6 induction in male adipose tissue. Further, macrophage activation markers such as CD68 as well as the pro-inflammatory activation markers CD11b and CD11c were higher in female adipose tissue. Interestingly, alcohol induced expression of TLR2, 3, 4, and 9 in female but not male adipose tissue, without affecting the TLR adaptor, MyD88. Higher trends of serum endotoxin in female mice may likely contribute to adipose tissue inflammation. In vitro chronic alcohol-mediated sensitization of macrophages to endotoxin is independent of sex. In summary, we demonstrate for the first time that there is a sexual dimorphism in alcohol-induced adipose tissue inflammation and female mice exhibit a higher degree of inflammation than male mice.
| S-EPMC5053524 | biostudies-literature
Project description:Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins (ECM) and formation of a fibrous scar. Hepatic Stellate Cells (HSCs) are the major source of Collagen Type I producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol-induced activation of human and mouse HSCs is not fully understood. We compared the gene expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n=3) or without underlying liver disease (n=4) using RNA-Seq analysis. Furthermore, the gene expression profile of ALD hHSCs was compared to that of alcohol-activated mHSCs (isolated from intragastric (IG) alcohol-fed mice), or carbon-tetrachloride (CCl4)-activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, and alcohol- and CCl4-activated mHSCs share the expression of common HSC activation (Col1a1, Acta1, PAI-1, TIMP1, LOXL2), indicating that a common mechanism underlies activation of human and mouse HSCs. Furthermore, alcohol-activated mHSCs most closely recapitulate the gene expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely upregulated in primary cultured alcohol-activated hHSCs and freshly isolated mHSCs, which include CSF1R, PLEK, LAPTM5, CD74, CD53, MMP9, CD14, CTSS, TYROBP, ITGB2, and other genes (compared to CCl4-activated mHSCs). We identified genes in alcohol-activated mHSCs from IG alcohol-fed mice that are largely consistent with the gene expression profile of primary cultured hHSCs from ALD patients. These genes are unique to alcohol-induced HSC activation in two species, and therefore, may become new targets or readout for anti-fibrotic therapy in experimental models of ALD.
2020-04-10 | GSE141100 | GEO
Project description:Craniofacial and CNS malformations characteristic of Fetal Alcohol Syndrome are caused by alcohol exposure during gastrulation (embryonic day [E]7 in mice; 2nd – 3rd week of human pregnancy). Genetics are a known contributor to differences in alcohol sensitivity in humans, and between different animal model strains such as C57BL/6J and C57BL/6NHsd mice. To investigate how these two genetically similar mouse strains differ in alcohol sensitivity, we profiled gene expression at baseline (E7.0) and 6 or 12 hours after alcohol exposure (E7.25–E7.5) in gastrulation-stage embryos. Many of the baseline transcriptional differences across strains were associated with immune signaling, indicative of their molecular divergence. Alcohol exposure was associated with a more pronounced transcriptional effect in 6J than in 6N, matching the 6J’s increased sensitivity. Alcohol exposure upregulated pathways related to cell death, stress, and hypoxia, and downregulated proliferation and morphogenic pathways. Dysregulated genes were also associated with craniofacial and CNS defects, but only in the 6J embryos. These data demonstrate the genetic variation that can contribute to the effects of prenatal alcohol and identify impacted molecular pathways, including higher baseline expression of inflammatory signaling genes in 6J embryos that likely increases sensitivity to teratogens such as alcohol. Collectively, our data provide a valuable resource that not only enables the discovery of biomarkers pertinent to prenatal alcohol exposure, but also facilitates the transcriptional comparison of two genetically similar mouse strains at three finely resolved developmental timepoints. To this end, we developed a web-based interactive tool to aid in data exploration available at http://parnell-lab.med.unc.edu/Embryo-Transcriptomics/.
2021-06-01 | GSE163796 | GEO
Project description:Alcoholic liver diseases (ALDs) encompass a broad spectrum of clinical features of alcoholic fatty liver, alcoholic steatohepatitis and cirrhosis, and increased risk of hepatocellular carcinoma. While the toxic effects of alcohol likely result from complex interactions between genes and the environment, the molecular mechanisms of alcohol-induced liver damage remains undefined. Thus, a better understanding of the mechanisms regulating hepatic cell injury may lead to more effective therapeutic approaches for ALD. Here we compared the miRNA expression profile from tissues from control mice and mice receiving intragastric ethanol feeding. Four microarray hybridization studies were performed on three different pairs of liver-derived RNA from intragastric ethanol feeding and normal mice. The miRNAs differentially overexpressed in livers from ethanol fed mice.
2014-10-07 | E-MTAB-2311 | biostudies-arrayexpress
Project description:In order to investigate the changes of hiPSC-CMS transcriptome after alcohol treatment and whether losartan has an effect on the changes of hiPSC-CM transcriptome after alcohol treatment, RNAseq was performed on hiPSC-CMs treated with 100mM alcohol and 100mM alcohol co-treated with1uM losartan.
2022-02-05 | GSE195981 | GEO
Project description:Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL17 Receptor A (IL17ra-/-), or pharmacological blockade of IL17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice, and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL17A positively correlated with the alcohol use in excessive drinkers, and was further increased in patients with ALD as compared to healthy individuals. Our data suggest that IL17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL17A may provide a novel strategy for treatment of alcohol-induced pathology.
2020-04-07 | GSE137228 | GEO
Project description:AimSex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences.MethodsPlacental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas.ResultsA total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10-7). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes.ConclusionThese data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.
| S-EPMC5331919 | biostudies-literature