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Alteration of hepatic gene expression profile in NPC mice correlates with tissue damage and oxidative stress status

ABSTRACT: Background: Niemann Pick type C disease (NPC) is a neurovisceral lipid storage disorder, characterized by unesterified cholesterol accumulation in lysosomal/late endosome compartments. The main tissues affected in the disease are the liver and the cerebellum. Although the primary defect in this disease occurs in the liver, the pathological mechanisms involved in hepatocyte damage and death have been poorly explored. Here, we assessed biochemical parameters, liver histology and the mRNA abundance of genes encoding proteins associated to oxidative stress, copper metabolism, fibrosis and inflammation and cholesterol metabolism in livers of WT and NPC mice. Methodology/Principal Findings: We found that the histology of NPC mice livers show signals of inflammation and fibrosis. This was correlated with an increase of carbonylated proteins and reduced glutathione content in the liver, as well as a significantly increment of total content of copper in liver tissue. Finally, we analyzed the liver gene expression pattern by qPCR and microarray assays. We found a correlation between the tissue fibrotic status and a differential hepatic expression of genes related to oxidative stress, fibrosis and inflammation processes in NPC mice. Conclusions/Significance: Our data show that NPC liver disease is evidenced by an increase in fibrosis as well as in oxidative stress status. Concomitantly, there is a correlation with an altered gene expression pattern, mainly of oxidative stress and fibrosis related genes, which could be useful as a potential disease progression biomarkers.

ORGANISM(S): Mus musculus

PROVIDER: GSE24013 | GEO | 2010/09/14

SECONDARY ACCESSION(S): PRJNA130369

REPOSITORIES: GEO

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Alteration of hepatic gene expression profile in NPC mice correlates with tissue damage and oxidative stress status

Project description:Background: Niemann Pick type C disease (NPC) is a neurovisceral lipid storage disorder, characterized by unesterified cholesterol accumulation in lysosomal/late endosome compartments. The main tissues affected in the disease are the liver and the cerebellum. Although the primary defect in this disease occurs in the liver, the pathological mechanisms involved in hepatocyte damage and death have been poorly explored. Here, we assessed biochemical parameters, liver histology and the mRNA abundance of genes encoding proteins associated to oxidative stress, copper metabolism, fibrosis and inflammation and cholesterol metabolism in livers of WT and NPC mice. Methodology/Principal Findings: We found that the histology of NPC mice livers show signals of inflammation and fibrosis. This was correlated with an increase of carbonylated proteins and reduced glutathione content in the liver, as well as a significantly increment of total content of copper in liver tissue. Finally, we analyzed the liver gene expression pattern by qPCR and microarray assays. We found a correlation between the tissue fibrotic status and a differential hepatic expression of genes related to oxidative stress, fibrosis and inflammation processes in NPC mice. Conclusions/Significance: Our data show that NPC liver disease is evidenced by an increase in fibrosis as well as in oxidative stress status. Concomitantly, there is a correlation with an altered gene expression pattern, mainly of oxidative stress and fibrosis related genes, which could be useful as a potential disease progression biomarkers. We compared three liver samples from NPC mice to a common reference sample made from pooled mRNA of three wild type mice

2010-09-14 | E-GEOD-24013 | biostudies-arrayexpress

ATP7B Gene Therapy of Autologous Reprogrammed Hepatocytes Alleviates Copper Accumulation in a Murine Model of Wilson’s Disease

Project description:Purpose：Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential, however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. Here we evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a murine model of WD Mathods and Results: By reprogramming hepatocytes from ATP7B-/- mice with small molecules, sufficient liver progenitor cells (LPCs) are harvested. After lentivirus-mediated miniATP7B gene transfection and re-differentiation, functional LPC-ATP7B-Heps are developed. RNA-seq data show that compared with LPC-GFP-Heps with enrichment of genes mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress pathways for copper ion binding and cell proliferation are enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviates deposition of excess liver copper with its associated inflammation and fibrosis, comparable to those observed using normal primary hepatocytes at four months after transplantation. Conclusion: We establish the autologous reprogrammed, ATP7B gene restored LPC-ATP7B-Heps and further transplantation demonstrate alleviated copper accumulation in WD mice.

2022-03-05 | GSE197948 | GEO

Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

Project description:LEC rats are considered as interesting model for studying hepatitis and development of hepatocarcinogenesis related to copper accumulation and oxidative stress. LEC rats have a mutation in a gene related to liver copper excretion, the Atp7b gene. As a consequence, this rat strain shows an abnormal copper accumulation in the liver. This is believed to be the origin of the acute hepatitis and the subsequent hepatocellular carcinoma that spontaneously develop in these rats. Here, we present the gene expression profiles of LEC rats at different disease stages. LEC rats were classified as normal 6 weeks old (6w), normal 9 weeks old (9w), slight jaundice and jaundice according to age and disease state. D-penicillamine, a copper chelator agent, blocks both hepatitis and tumor development. D-penicillamine-trated LEC rats were used as control rats for gene expression comparison as they showed neither hepatitis development nor tumor marker expression. Gene expression differences in protein metabolism and tumor marker proteins add to the known oxidative stress and inflammation characterization of the hepatitis process, leading to new insights concerning hepatitis and hepatocarcinogenesis development. Keywords: disease state analysis 6 weeks old LEC rats, 6 rats per group, were sacrified at different hepatitis stages. Biochemical and histological analyses were performed in order to classify the rats into normal, slight jaundice or jaundice groups. D-penicillamine-treated LEC rats (100 mg/kg/day p.o.) were used as control rats since they behave as normal rats. Microarray analysis was performed on liver samples, one replicate per rat, using dyes swap.

2008-04-24 | E-GEOD-7654 | biostudies-arrayexpress

Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

2008-04-25 | GSE7654 | GEO

Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents

Project description:C57BL/6 mice received methionine/choline deficient (MCD) diet to establish the model of non-alcoholic fatty liver disease (NAFLD) with or without Diethyldithiocarbamate (DDC) treatment. DDC improves hepatic steatosis, ballooning, inflammation and fibrosis in rodent models of NAFLD through modulating lipid metabolism and oxidative stress.

2018-12-26 | GSE113843 | GEO

Loss of hepatic Mboat7 leads to liver fibrosis

Project description:Objective: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. Design: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7 Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. Results: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7 Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7 Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol (LPI) levels. The altered LPI and phosphatidylinositol subspecies in MBOAT7 Δhep livers and humans rs641738TT carriers were similar. Conclusion: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

2020-06-30 | GSE139992 | GEO

Gene expression in liver of morbidly obese patients

Project description:Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease affecting 20-30% of the population in developed countries. NAFLD is strongly associated with abdominal obesity and is recognized as the hepatic manifestation of the metabolic syndrome. In a subgroup of patients with NAFLD inflammation and fibrosis develops, this so-called Non-Alcoholic Steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. A multi-hit hypothesis has been proposed in which during the first “hit” fat accumulation occurs in hepatocytes from excessive delivery of fatty acids from adipose tissue, in addition there is an imbalance in lipid synthesis and export. However, the reason why fat accumulation is subsequently followed by inflammation and fibrosis in some patients is poorly understood. We studied the role of gene expression at the transcriptional level using microarray in bariatric patients from whom the liver histology was available. Patients scheduled for bariatric surgery were recruited in Pretoria/South-Africa. At the time of the procedure, tissue samples of the visceral and subcutaneous fat were taken for molecular analysis as well as liver tissue for histology, also full biochemical data was collected. Patients were grouped according histology: group I (<5% steatosis), group II (NAFLD, 30-50% steatosis) and group III (NASH). The 15 samples were used for microarray (nr patients respectively for stages I-II-III: 6-4-5).This dataset is part of the TransQST collection.

2015-07-02 | E-GEOD-59045 | biostudies-arrayexpress

Influence of dietary sucrose and copper content in a rat model of non-alcoholic fatty-liver disease

Project description:Nutrigenomics analysis was used to investigate the molecular responses to dietary Cu deficiency independently and in combination with 30% (w/w) sucrose in a mature rat model of NAFLD. Low Cu significantly decreased hepatic and serum Cu, and induced NAFLD-like histopathology, mild steatosis, up-regulated transcripts in inflammation and hepatic stellate cell activation, and significantly increased oxidative stress. Rats fed low Cu together with 30% sucrose also developed insulin resistance, increased ATP citrate lyase and FASN expression, and greater oxidative stress. High sucrose with adequate Cu also promoted inflammation and fibrosis, but not steatosis. This study indicates that low dietary Cu and sucrose consumption are singular and synergistic dietary factors in promotion of NAFLD and NASH that act independently of obesity or severe steatosis, likely by promoting oxidative stress and activation of inflammation and fibrosis. Mature (6 months old) male Wistar Rats that had been allowed ad libitum access to Mazuri rodent pellets were used in the study. Twenty-four rats were divided into four groups and fed for 12 weeks with diets based on the Purified AIN76A formulation, modified for target sucrose and Cu content (Custom Animal Diets, Bangor, NJ). Sucrose and copper content in diets were as follows: ‘A’ CuD/30%- Cu deficient (<0.3 mg Cu/kg)/30% sucrose, ‘B’ CuA/30%- Cu adequate (125 mg/kg)/30% sucrose, ‘C’ CuD/10%- <0.3 mg/kg Cu/10% sucrose, and ‘D’ CuA (125 mg/kg Cu)/10% sucrose (control). Starch and dextrin were used to equalize carbohydrates.

2015-06-26 | E-GEOD-58875 | biostudies-arrayexpress

The TMAO Generating Enzyme Flavin Monooxygenase 3 is a Central Regulator of Cholesterol Balance

Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation. To identify potential regulators of macrophage reverse cholesterol transport (RCT), liver was isolated from two independent mouse models where the non-biliary RCT pathway known as transintestinal cholesterol excretion (TICE) was either chronically (NPC1L1-liver-transgenic mice) or acutely (ACAT2 antisense oligonucleotide treatment) stimulated. Total RNA was isolated and gene expression levels were profiled on the Affymetrix GeneAtlas MG-430 PM Array Strip (Affymetrix; Santa Clara, CA, USA)

2014-12-19 | E-GEOD-64326 | biostudies-arrayexpress

The loss of paraoxonase-2 activity aggravates lipid accumulation, mitochondrial dysfunction, and oxidative stress through the impaired autophagy pathway in in vitro fatty liver model

Project description:Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immunometabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is associated with diverse features including oxidative stress, impaired mitochondrial function andlipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and investigation into a potential drug target that has overarching effects on these features will provide benefits towards discovering effective treatments for NAFLD. Here, we examined the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in in vitro fatty liver model. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic condition, and our transcriptome analysis revealed that PON2 deficiency disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, liver fibrosis, and hepatic inflammation. PON2 promoted the activation of overall autophagy pathway, especially mitophagy cargo sequestration, which may be considered as an underlying mechanism that contributed to the role of PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide mechanistic foundation on the prospect of targeting PON2 for the development of novel therapeutics for NAFLD in the future.

2022-09-26 | GSE213653 | GEO

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