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Microarray analysis among non-alcoholic fatty liver, non-alcoholic steatohepatitis, and type 2 diabetes mellitus rats

ABSTRACT: Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE65220 | GEO | 2015/01/23

SECONDARY ACCESSION(S): PRJNA273424

REPOSITORIES: GEO

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Microarray analysis among non-alcoholic fatty liver, non-alcoholic steatohepatitis, and type 2 diabetes mellitus rats

Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.

2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress

HEPATIC TRANSCRIPTOME SIGNATURES IN PATIENTS WITH VARYING DEGREES OF NON-ALCOHOLIC FATTY LIVER DISEASE COMPARED TO HEALTHY NORMAL-WEIGHT INDIVIDUALS

Project description:Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over non-alcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared to healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis was performed on liver biopsies obtained from healthy normal weight (n=14) and obese (n=12) individuals, NAFL (n=15) and NASH (n=16) patients. Normal weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared to NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD.

2019-02-22 | GSE126848 | GEO

Differential analysis of gene expression in liver tissues of patients with nonalcoholic fatty liver disease and controls.

Project description:Non-alcoholic fatty liver disease (NAFLD) comprises a collection of chronic liver disorders distinguished by the excessive accumulation of lipids within hepatocytes and the presence of steatosis. It covers a range of liver conditions that vary from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH). In this study, hepatic gene expression was compared among 6 patients with NAFL, 4 with NASH, and 6 healthy controls. Subsequently, differential genes were identified through comparative analysis of sequencing results, and target genes potentially related to the pathogenesis of NAFLD were further investigated. Numerous potential target genes and pathways have been identified in NAFLD, providing potential targets for therapeutic interventions.

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Expression data from human non-alcoholic fatty liver disease stages

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2014-11-07 | E-GEOD-63067 | biostudies-arrayexpress

The methyltransferase MLL4 promotes non-alcoholic steatohepatitis by enhancing NF-κB signaling

Project description:Non-alcoholic fatty liver disease (NAFLD) is a growing health problem worldwide, ranging from non-alcoholic fatty liver (NAFL) to the more severe metabolic non-alcoholic steatohepatitis (NASH). Although many studies have elucidated the pathogenesis of NAFLD, the epigenetic regulatory mechanism from NAFL to NASH remains incompletely understood. The histone H3 lysine 4 methyltransferase, MLL4 (also called KMT2D), is a critical epigenetic transcriptional coactivator that mediates overnutrition-induced steatosis in mice, but its potential role in the progression of NASH remains largely unknown. Here, we show that mice lacking the one allele of the Mll4 gene are resistant to hepatic steatosis, inflammation, and fibrosis in NASH conditions compared to wild-type controls. Transcriptome analysis of the livers of control and Mll4+/- mice identified pro-inflammatory genes regulated by the nuclear factor kappa B (NF-κB) signaling pathway as major target genes of MLL4. We show that MLL4 binds to p65 and that MLL4 is required for NF-κB transactivation. Myeloid-specific Mll4 knockout mice showed an almost complete block of NASH, while hepatocyte-specific Mll4 knockout mice showed mild inhibition of steatosis. Pro-inflammatory M1 polarization is decreased and anti-inflammatory M2 polarization is increased in liver macrophages from myeloid-specific Mll4 knockout mice. Importantly, we show that histone H3-lysine 4 methylation mediated by the MLL4-complex plays a critical role in promoting the expression of Ccl2 in hepatocytes and M1 marker genes in macrophages. Our results demonstrate that MLL4, through the NF-κB-MLL4 regulatory axis, exacerbates steatohepatitis in the context of an inflammatory response and represents a potential therapeutic target for NASH.

2024-11-18 | GSE277545 | GEO

Post-transplant (non-alcoholic steatohepatitis) NASH compared with transplanted normal controls

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2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress

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Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes but their molecular pathogenesis is not fully elucidated. Global RNA sequencing of snap frozen liver tissue from 98 patients with biopsy-proven NAFLD was performed. Unsupervised hierarchical clustering well-distinguished NASH from NAFL, and NASH patients exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified multiple secreted proteins upregulated in NASH and/or advanced fibrosis

2021-05-31 | GSE167523 | GEO

NASH

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays

2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress

Tid1 Deficiency Disrupting Mitochondria to Drive NASH-Dependent Hepatocellular Carcinoma Progression

Project description:Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor for hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation; meanwhile, sequentially developed fatty liver, NASH, and cirrhosis/HCC in a diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that play a key role in the NASH-dependent HCC development. Overall, we established a new mouse model that develops NASH-dependent HCC and provides a promising approach to improve the treatment.

2022-06-02 | E-MTAB-9973 | biostudies-arrayexpress

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Project description:Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the hepatic manifestations of metabolic syndrome. Histological assessment of liver biopsies is the gold standard for diagnosis of NASH. A Liver biopsy is resource heavy and can lead to complications such as bleeding and, moreover, does not fully capture the tissue heterogeneity of the fibrotic liver. Therefore, non-invasive biomarkers that can reflect an integrated state of the liver is highly needed to improve diagnosis and sampling bias. Hepatic stellate cells (HSCs) are central in development of hepatic fibrosis, a hallmark of NASH. Secreted HSC-specific proteins may, therefore, reflect disease state in the NASH liver and thereby serve as non-invasive diagnostic biomarkers. We performed RNA-sequencing on liver biopsies from a discovery cohort (n = 30) of histological characterised obese patients (body mass index > 35 kg/m2) to identify and evaluate HSC-specific genes encoding secreted proteins. Bioinformatical analysis was used to identify potential biomarkers and their expression at single-cell resolution. We validated our findings by single-molecule fluorescence in situ hybridization (smFISH) and ELISA to detect mRNA in liver tissue and protein levels in plasma, respectively. Hepatic expression of SPARC-related modular calcium-binding protein 2 (SMOC2) was increased in NASH (steatosis ≥ 1, lobular inflammation ≥ 1, and hepatocyte ballooning ≥ 1) compared no-NAFLD (p.adj < 0.001). Single-cell RNA-sequencing data indicated SMOC2 expression by HSCs, which was validated using smFISH. Moreover, plasma SMOC2 was elevated in NASH compared to no-NAFLD (p < 0.001) with a predictive accuracy of AUROC 0.88. In conclusion, we propose increased SMOC2 in plasma reflects HSC activation, a key cellular event associated with NASH progression, and may serve as a non-invasive biomarker of NASH.

2022-11-02 | GSE207310 | GEO

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