Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA488808 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7775080.fastq.gz | Fastqsanger.gz | |||
| SRR7775071.fastq.gz | Fastqsanger.gz | |||
| SRR7775081.fastq.gz | Fastqsanger.gz | |||
| SRR7775072.fastq.gz | Fastqsanger.gz | |||
| SRR7775082.fastq.gz | Fastqsanger.gz |
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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:ObjectiveNonalcoholic 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.MethodsWe 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.ResultsRNA 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.ConclusionsGlobal 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.
| S-EPMC6358550 | biostudies-literature
Project description:We applied RNA sequencing (RNA-seq) to study the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse model of NASH. GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16, or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. We find that chow reversal promoted substantial benefits on metabolic, biochemical and histological outcomes accompanied by marked suppression of gene expression markers of hepatocellular senescence in GAN DIO-NASH mice. These therapeutic benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.
2024-01-16 | GSE246328 | 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:To investigate the role of hepatic Pck1 in diet-induced nonalcoholic steatohepatitis (NASH), liver-specific Pck1-knockout mice were developed with Alb-Cre. Wild-type (WT) and Pck1-cKO mice were fed a Chow diet (Research Diets, D12450J: 10% Kcal fat, with tap water) or NASH-inducing diet (Research Diets, D12492: 60% Kcal fat, with drinking water containig 23.1 g/L fructose and 18.9 g/L glucose) for 24 weeks. RNA was extracted from the livers of mice from all treatment groups and used for RNA seqencing. RNA-seq data demonstrated that gluconeogenic enzyme PCK1 deficiency played an important role in the development of NASH.
2023-02-07 | GSE162211 | 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: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
Project description:To investigate the mechanism of hepatic Activin A and Gpnmb in NAFLD/NASH, we studied C57BL/6J mice on a FPC NASH diet and sugar water for 16 weeks, compared with standard chow diet, and used adeno-associated viral vectors with a liver-specific thyroxine binding globulin (TBG) promoter to express Activin A or GFP (control), or AAV8-H1-shRNA to knockdown of Gpnmb or scramble control in NAFLD/NASH liver. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different livers in each group.
2024-04-09 | GSE221443 | GEO
Project description:To investigate the alterlation of liver gene expression in diet-induced NASH model with adipose tissue insulin resistance, we evaluated liver of control mice and adipocyte-specific PDK1 knockout (PDK1KO) mice fed either normal chow(NC) or Gubra amylin NASH (GAN) diet for 16weeks after weaning at 4 weeks old. We then performed gene expression profiling analysis using data obtained from RNA-seq of these 4 groups.
2022-11-09 | GSE216128 | GEO
Project description:To investigate the alterlation of eWAT gene expression in diet-induced NASH model with adipose tissue insulin resistance, we evaluated eWAT of control mice and adipocyte-specific PDK1 knockout (PDK1KO) mice fed either normal chow(NC) or Gubra amylin NASH (GAN) diet for 16weeks after weaning at 4 weeks old. We then performed gene expression profiling analysis using data obtained from RNA-seq of these 4 groups.
2023-02-11 | GSE224733 | GEO