Transcriptomics driven metabolic pathway analysis reveals similar metabolic alterations in diet- and chemical-induced mouse NASH model and human
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ABSTRACT:
PROVIDER: PRJNA962044 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24313740_1.fastq.gz | Fastqsanger.gz | |||
| SRR24313740_2.fastq.gz | Fastqsanger.gz |
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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and can rapidly progress to non-alcoholic steatohepatitis (NASH). Accurate preclinical models and robust methodologies need to be established to understand the underlying metabolic mechanisms and develop treatment strategies. Based on our meta-analysis of currently available data on several mouse models, we hypothesized a diet- and chemical-induced NASH model closely resembles metabolic alteration in human. We developed an already established WD+CCl4-induced NASH model. We developed and performed transcriptomics driven metabolic pathway analysis (TDMPA) using differentially expressed genes in mouse NASH liver compared to control. We compared the altered metabolic pathways and enzymatic reactions to human NASH. We performed functional assays and lipidomics to confirm our findings related to metabolic alterations. Numerous metabolic pathways were altered in human NASH and mouse model. De novo triglyceride biosynthesis, fatty acid beta-oxidation, bile acid biosynthesis, cholesterol metabolism, and oxidative phosphorylation were the most influenced pathways. We confirmed significant reduction in mitochondrial functions and bioenergetics in NASH model, and in acylcarnitines. We identified a wide range of lipid species within the most perturbed pathways predicted by TDMPA. Triglycerides, phospholipids and bile acids were increased significantly in NASH, confirming our initial observations. We identified several metabolic pathways that typify NASH pathophysiology in human. By comparing human and mouse metabolic signatures, we evaluated metabolic resemblance of mouse model to human and its suitability for the study of the disease and potential usage for drug discovery and testing. We also presented TDMPA, a novel methodology to evaluate metabolic pathway alterations in metabolic disorders and a valuable tool for defining metabolic space to aid experimental design for lipidomics and metabolomics approaches.
2024-03-06 | GSE230639 | GEO
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
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
Project description:Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or nonalcoholic steatohepatitis (NASH). While increasing HCC risk, NASH triggers TP53-dependent hepatocyte senescence, which we found to parallel hypernutrition-induced DNA breaks. How this tumor-suppressive response is bypassed to license accumulation of oncogenic mutations and enable HCC progression was previously unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target that is elevated in senescent-like NASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically-stressed premalignant disease-associated hepatocytes and HCC progenitor cells, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and TP53 degradation AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing NRF2-FBP1-AKT-TP53 metabolic switch, operative in mice and humans, also enhances proliferation-enabled accumulation of DNA damage-induced somatic mutations that drive NASH to HCC progression.
2025-01-10 | GSE266447 | GEO
Project description:Hepatocellular carcinoma (HCC), the third most common cancer, originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged primarily by viruses or nonalcoholic steatohepatitis (NASH)1,2. While increasing HCC risk3, NASH also induces TP53-dependent hepatocyte senescence4. How this tumor-suppressive response is activated but eventually bypassed to license HCC progression is unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target, induced in senescent NASH hepatocytes but downregulated in most human HCCs. Initial FBP1 downregulation in disease-associated hepatocytes, whose accumulation precedes HCC development5, activates AKT to inhibits GSK3 substrate binding, thereby augmenting activation of NRF2 which accelerates FBP1 and TP53 degradation. Intrinsic NRF2 activation and FBP1 loss trigger overlapping transcriptomic responses that suppress senescence, enhance hepatocyte proliferation and metabolism, and enable NRAS- or NASH-induced hepatocarcinogenesis. This AKT-dependent metabolic switch, operative in mice and humans, controls NASH to HCC progression. Our results further suggest that NASH-related hepatocyte senescence is triggered by hypernutrition-induced single strand DNA breaks. Senescence reversal enables HCC progenitor expansion and somatic mutagenesis.
2024-07-15 | GSE240047 | GEO
Project description:OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current study are to delineate the transcriptomic and proteomic signatures of NASH liver, to identify potential pathogenic pathways and factors, and to critically assess their role in NASH pathogenesis. METHODS: We performed RNA sequencing and quantitative proteomic analyses on the livers from healthy and diet-induced NASH mice. We examined the association between plasma levels of TSK, a newly discovered hepatokine, and NASH pathologies and reversal in response to dietary switch in mice. Using TSK knockout mouse model, we determined how TSK deficiency modulates key aspects of NASH pathogenesis. RESULTS: RNA sequencing and quantitative proteomic analyses revealed that diet-induced NASH triggers concordant reprogramming of the liver transcriptome and proteome in mice. NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK, whereas dietary switch reverses NASH pathologies and reduces circulating TSK concentrations. Finally, TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling. CONCLUSIONS: Global transcriptomic and proteomic profiling of healthy and NASH livers revealed the molecular signatures of diet-induced NASH and dysregulation of the liver secretome. Our study illustrates a novel pathogenic mechanism through which elevated TSK in circulation promotes NASH pathologies, thereby revealing a potential target for therapeutic intervention.
2019-01-08 | GSE119340 | GEO
Project description:Current models of hepatocellular tumorigenesis propose that the chronic injury and inflammation in NASH are mutagenic and growth promoting which can eventually lead to HCC. However, contrary to this model, here we show that NASH suppresses the early development of liver cancers in mice. We found that NASH did not hinder the malignant reprogramming of oncogene expressing hepatocytes but suppressed their clonal expansion and led to their elimination. This elimination was not caused by a direct effect of NASH on malignant cells but due to the stimulation of cell competition in tumor-surrounding hepatocytes. Mechanistically, NASH activated the Hippo pathway effectors Yap and Taz in hepatocytes, which elevated their cellular fitness. Thus, deletion of Yap/Taz in tumor-surrounding hepatocytes abolished the elimination of tumor cells by NASH, while experimental hyperactivation of Yap in malignant cells protected them from NASH-induced elimination
2025-09-01 | GSE241856 | GEO
Project description:Non-alcoholic steatohepatitis (NASH), which is increasing in incidence due to the obesity epidemic, is a T-cell mediated, auto-aggressive condition that can result in progressive liver disease and hepatocellular carcinoma (HCC). The gut-liver axis contributes to NASH, yet mechanisms underlying metabolic T-cell activation and NASH-related fibrosis have largely remained elusive. We found that gastrointestinal B-cells are activated and increased in number in mouse/human NASH, allowing metabolic T-cell activation to induce NASH antigen- and microbiota-independently. Genetic/therapeutic depletion of B-cells systemically or of gastrointestinal B-cells specifically, prevented or reverted NASH and fibrosis. Secretion of immunoglobulins was essential for NASH and fibrosis development. IgA secretion was necessary for fibrosis-induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcRγ signaling-axis. Furthermore, clinical/molecular analyses from NASH-patients demonstrated IgA and activated FcRγ+ hepatic myeloid cells to correlate with the degree of liver-fibrosis. Thus, gastrointestinal B-cells and the IgA-FcRγ signaling-axis on hepatic myeloid cells represent potential therapeutic targets to treat NASH.
2023-11-22 | GSE190204 | GEO
Project description:Whole liver from mice with diet-induced nonalcoholic fatty liver disease (NASH) was subjected to bulk RNA-seq. Ingenuity pathway analysis implicated pathways related to the leukocyte adhesion and differentiation in the pathogenesis of NASH. Among the adhesion molecules expressed in endothelial cells, only Icam1 (Log2FC: 1.99; FDR: 1.55E-37) and Vcam1 (Log2FC: 1.93; FDR: 9.32E-35) were differentially upregulated in NASH liver.
2021-02-01 | GSE164084 | GEO
Project description:Human genetic studies have identified several MARC1 variants as protective against non-alcoholic fatty liver diseases (NAFLD). The MARC1 variants are associated with reduced lipid profiles, liver enzymes, and liver-related mortality. However, the role of mitochondrial amidoxime reducing component 1 (mARC1), encoded by MARC1, in NAFLD is still unknown and the therapeutic potential of this target has never been developed. Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine conjugated mouse mARC1 siRNA to address this. In ob/ob mice, knockdown of mARC1 in mouse hepatocytes resulted in decreased liver weight, serum lipid enzymes, low-density lipoprotein cholesterol, and liver triglycerides. Loss of mARC1 also improved the lipid profiles and attenuated liver pathological changes in two diet-induced nonalcoholic steatohepatitis (NASH) mouse models. A comprehensive analysis of mARC1-deficient liver in NASH by metabolomics, proteomics, and lipidomics showed that mARC1 knockdown partially restored metabolites and lipids altered by diets. Taken together, loss of mARC1 protects mouse liver from NASH, suggesting a potential therapeutic approach of NASH by downregulation of mARC1 in hepatocytes.
2023-04-28 | MSV000091820 | MassIVE