Tid1 Deficiency Disrupting Mitochondria to Drive NASH-Dependent Hepatocellular Carcinoma Progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB42251 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5023360.fastq.gz | Fastqsanger.gz | |||
| ERR5023361.fastq.gz | Fastqsanger.gz | |||
| ERR5023362.fastq.gz | Fastqsanger.gz | |||
| ERR5023363.fastq.gz | Fastqsanger.gz | |||
| ERR5023364.fastq.gz | Fastqsanger.gz |
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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:Mitochondrial calcium signaling plays a critical role in mitochondrial homeostasis during non-alcoholic steatohepatitis (NASH) progression. Here, we report Ras‐GTPase activating protein SH3 domain‐binding protein 1 (G3BP1), a core protein of stress granule (SG), significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Hepatocyte-specific G3BP1 deficiency attenuates NASH in two dietary mouse models. SG and the mitochondrial import protein TOM70 collaboratively mediate the translocation of G3BP1 to the mitochondria. G3BP1 interacts and stabilizes mitochondrial calcium uptake 1 (MICU1) via inhibiting YME1L1-mediated degradation of MICU1, and also impedes MCU complex activity and assembly, leading to mitochondrial calcium overload. Moreover, metabolic stress suppresses TRIM25-mediated K63-ubiquitination of G3BP1 and subsequent SG disassembly. Pharmacological inhibition of G3BP1 impairs the G3BP1-MICU1 interaction and prevents mitochondrial homeostasis imbalance and NASH progression. Collectively, we uncover the significant role of mitochondrial G3BP1 in mitochondrial homeostasis and NASH progression, which provides a potential target for therapeutic interventions.
2023-12-13 | GSE249869 | 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:Mitochondrial calcium signaling plays a critical role in mitochondrial homeostasis during non-alcoholic steatohepatitis (NASH) progression. Here, we report Ras‐GTPase activating protein SH3 domain‐binding protein 1 (G3BP1), a core protein of stress granule (SG), significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Hepatocyte-specific G3BP1 deficiency attenuates NASH in two dietary mouse models. SG and the mitochondrial import protein TOM70 collaboratively mediate the translocation of G3BP1 to the mitochondria. G3BP1 interacts and stabilizes mitochondrial calcium uptake 1 (MICU1) via inhibiting YME1L1-mediated degradation of MICU1, and also impedes MCU complex activity and assembly, leading to mitochondrial calcium overload. Moreover, metabolic stress suppresses TRIM25-mediated K63-ubiquitination of G3BP1 and subsequent SG disassembly. Pharmacological inhibition of G3BP1 impairs the G3BP1-MICU1 interaction and prevents mitochondrial homeostasis imbalance and NASH progression. Collectively, we uncover the significant role of mitochondrial G3BP1 in mitochondrial homeostasis and NASH progression, which provides a potential target for therapeutic interventions.
2024-08-18 | GSE274650 | GEO
Project description:To identify mitochondria-encoded circRNA in HCC, we isolated mitochondria and performed RNA sequencing of HCC tissues
2023-03-06 | GSE226253 | GEO
Project description:G3BP1 translocates into mitochondria to impair MCU complex function and promotes NASH progression
| PRJNA1051061 | ENA
Project description:BACKGROUND & AIMS: Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. METHODS: Microarray was performed to identify differentially expressed genes in NASH. Quantitative real time PCR (qRT-PCR) was used to examine gene expression levels. Western blotting and immunofluorescence staining were employed to examine hemoglobin proteins. Flow cytometry was used to measure intracellular oxidative stress. RESULTS: Analysis of microarray gene expression data has revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopspies from NASH patients. Increased hemoglobin expression in NASH was validated by qRT-PCR. However, the expression of erythrocyte specific marker genes such as SPTA, SPTB, GYPA, GATA1, and ALAS2 did not change, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, induced a dose dependent increase in HBA1 expression in HepG2 cells. Intriguingly, forced hemoglobin expression suppressed oxidative stress. CONCLUSIONS: Oxidative stress upregulates hemoglobin expression in hepatocytes. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage. These findings suggest that hemoglobin is an inducible antioxidant in hepatocytes in response to increased oxidative stress as found in NASH livers. Twelve biopsy diagnosed NASH patients were included in this study. For control groups, total RNA from 5 different subjects were purchased from ADMET. These subjects are free from liver disease.
2010-10-20 | E-GEOD-24807 | biostudies-arrayexpress
Project description:mitochondria-encoded circRNA in Hepatocellular Carcinoma
| PRJNA939238 | ENA
Project description:Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), that often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC both depend on inflammatory signaling whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways. Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition as well as in DEN-induced HCC. We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis however, independent of its role in NFB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans. Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients.
2022-12-08 | GSE146049 | GEO
Project description:Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening public health, however its natural history is poorly understood. Unlike ob/ob mice, Lep∆I14/∆I14 rats develop unique NASH phenotype with an inflection point of inflammation at postnatal week 16. Using Lep∆I14/∆I14 rats, we studied the natural history of NASH progression by performing an integrated analysis of hepatic transcriptome from postnatal week 4 to 48. Leptin deficiency leads to the precipitously increasing expression of genes encoding rate-limiting enzymes in lipid metabolism. However, hepatic inflammation related genes, pathways and immune-cell infiltration are restricted after week 16, implying an essential role of LEPTIN in regulating hepatic inflammation. Lep∆I14/∆I14 rats share more genes with NASH patients than known mouse models, therefore will provide a better genetic platform for studying NASH than mice.
2019-12-31 | GSE124002 | GEO