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Bile acid therapeutics for NASH

ABSTRACT: We studied the effect of AAV8-TBG-FGF15 and GSK2330672 (8mg/kg/day), alone or in combination, against diet-induced NASH and fibrosis in mice

ORGANISM(S): Mus musculus

PROVIDER: GSE168069 | GEO | 2021/08/11

REPOSITORIES: GEO

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Bile acid therapeutics for NASH

Project description:Bile acid therapeutics for NASH

| PRJNA705980 | ENA

Effect of hepatocyte-specific PPARgamma knock out with and without rosiglitazone treatment in hepatic gene expression of mice with diet-induced NASH

Project description:In this study we sought to determine if the knockout of hepatocyte PPARgamma expression alter transcriptomics of the livers of mice with diet-induced NASH, and if there was a hepatocyte-specific PPARgamma dependent regulation of gene expression in TZD treated mice. Specifically, adult PPARg floxed male mice were fed a high fat, cholesterol and fructose (HFCF) diet for 24 weeks. After this period of time, half of the mice were injected with AAV8-TBG-Cre to knockout PPARgamma in hepatocytes (KO mice). The other half of the mice were injected with AAV8-TBG-Null, and served as controls (C mice). A subset of PPARg floxed mice were fed a low fat, cholesterol and fructose (LFCF) diet, and they were injected with AAV8-TBG-Null to generate LFCF-controls. Two weeks after AAV8 injections, half of the HFCF-fed mice in each group (C and KO) were switched to a HFCF diet containing rosiglitazone maleate (TZD, 50mg/kg of diet) for eight additional weeks. Mice were kept in their respective diets for 8 additional weeks too. At the end of the study, the livers were collected to assess hepatic gene expression with RNA-seq (performed by Novogen, Inc.)

2021-01-15 | GSE162276 | GEO

Shp-deletion induces dissociation of steatosis and inflammation in NASH

Project description:Two months-old Shp flox/flox male mice were injected with either AAV8 expressing Cre recombinase driven by the thyroxine-binding globulin (Tbg) promoter (AAV8-Tbg-Cre) or control AAV8 (AAV8-Tbg-null) and fed chow or a diet enriched in high fat, cholesterol, and fructose (Research diet D09100301: 40 kcal% fat, 2% cholesterol, 20 kcal% fructose, hereafter referred to as HFCF diet) for 3 months. Liver RNA was isolated and submitted to RNA-seq.

2019-12-10 | GSE133566 | GEO

Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death

Project description:Regulation of RNA processing contributes profoundly to tissue development and physiology. The serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Accumulation of lipids in SRSF1-deficient hepatocytes is quickly followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. This pathogenesis is recapitulated in SRSF1-depleted human liver cancer cells illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. This data set contains a proteomic comparison of hepatocytes from wild type vs. acute knockout of SRSF1. The acute knockout was generated by injecting 8-week-old SRSF1 fl/fl mice with a viral vector expressing Cre under the control of the liver-specific thyroxine binding globulin (TBG) promoter (AAV8-TBG-iCre). Controls were generated by injecting AAV8-TBG-GFP viral vector. The hepatocytes were isolated 2 weeks post injection.

2023-03-11 | PXD027035 | Pride

Effect of Activin A and Gpnmb on gene expression in NAFLD/NASH liver in C57BL/6J mice and gene expression change in C57BL/6J mice fed on sugar water-NAFLD/NASH diet compared with standard chow diet

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

Effect of hepatocyte-specific PPARgamma knock out in the regulation of hepatic gene expression in mice fed a low fat diet or and high fat, cholesterol and fructose diet that induces NASH

Project description:In this study we sought to determine how hepatocyte-specific PPARgamma expression regulates hepatic gene expression in normal (healthy) mice fed a LFCF diet, or mice that were fed a HFCF diet for 24 weeks to induce non-alcoholic steatohepatitis (NASH). Specifically, we used chow-fed adult (10 week-old) PPARgamma floxed male mice and injected them with AAV8-TBG-Cre to knockout PPARgamma in hepatocytes (KO). A subset of PPARgamma floxed mice were injected with AAV8-TBG-Null to generate controls (C). Two weeks after AAV injections, half of the mice in each group were fed a low fat, cholesterol and fructose (LFCF) diet, or a high fat, cholesterol and fructose (HFCF) diet for 24 weeks. Livers were collected at the end of the study to assess hepatic gene expression with RNA-seq (performed by Novogen, Inc.)

2021-01-15 | GSE162249 | GEO

Benchmarking AAV-Cre mouse models for RNA-seq

Project description:This study reports the baseline effects of systemic (i.v.) administration of AAV8-TBG-null and AAV8-TBG-Cre on the liver of male, wild-type C57Black6/J mice. We performed polyA RNAseq of whole liver lysates from mice 2, 4 and 7 days post AAV8-TBG-null or AAV8-TBG-Cre administration and compared their transcriptome with that of male mice of similar age that didn't receive any AAV8 (day 0). We report some changes in gene expression of genes related to circadian rythm and response to infection at certain timepoints. Our results demonstrate that AAV8-TBG vectors can have minimal effects on the murine liver transcriptome, something that needs to be considered and controlled when using this system for mouse experiments. Finally, we hope that this dataset will help other researchers to correctly interpret data obtained from mouse experimentation using AAV8-TBG vectors.

2021-06-01 | GSE165651 | GEO

Transcriptome profiling of GATA4 depleted hepatocytes

Project description:Analysis of changes in gene expression following hepatocyte specific deletion of GATA4 in adult mice. Results showed that the subset of differentially expressed genes had liver specific ontologies. Total RNA isolated from hepatocytes of AAV8-Tbg-Cre injected GATA4 fl/fl mice was compared to total RNA isolated from AAV-Tbg-GFP injected GATA4 fl/fl mice.

2013-11-07 | E-GEOD-49130 | biostudies-arrayexpress

Transcriptome profiling of GATA4,6 double depleted hepatocytes

Project description:Analysis of changes in gene expression following hepatocyte specific deletion of GATA4 and GATA6 in adult mice. Results showed that the subset of differentially expressed genes had liver specific ontologies. Total RNA isolated from hepatocytes of AAV8-Tbg-Cre injected GATA4,6 fl/fl mice was compared to total RNA isolated from AAV-Tbg-GFP injected GATA4,6 fl/fl mice.

2013-11-07 | E-GEOD-51478 | biostudies-arrayexpress

Effect of hepatocyte-specific PPARgamma (PPARg)expression and diet-induced NASH in the liver transcriptome of male and female mice with pre-stablished diet-induced obesity

Project description:Adult PPARg floxed male and female mice were fed a high fat diet (HFD) for 16 weeks to induce obesity. Half of these mice were then injected with AAV8-TBG-Cre to knockout PPARg in hepatocytes. The remaining half were injected with AAV8-TBG-Null to generate control mice. After two weeks, mice fed the HFD were either maintained on this diet or switched to a high fat, high cholestrol, high fructose (HFCF) diet for an additional 16 weeks. This study was designed to examine whether the loss of hepatocyte PPARg in mice with established obesity would alter the liver transcriptomics in a PPARg dependent manner when the mice are fed a HFD or a HFCF diet.

2023-01-11 | GSE200352 | GEO

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