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Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

ABSTRACT: We exposed three mouse strains to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. Comprehensive methylation and transcriptomic analysis found overlapping but also highly divergent changes in DNA methylation and gene expression, with pathway analysis suggesting a strategy for strain-specific targeted pharmacologic intervention of upstream regulators. Administeration of the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway resulted in genotype-specific protection against dietary effects in BL6 as predicted by our epigenetic analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE215954 | GEO | 2023/10/17

REPOSITORIES: GEO

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Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.

Project description:Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.

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Altered mRNA expression profile of GW4064 treated mouse livers compared to vehicle control

Project description:Farnesoid X receptor (FXR) is a ligand activated nuclear receptor belonging to the nuclear receptor superfamily. Bile acids (BAs) are the endogenous ligand for FXR. FXR is a master regulator of BA homestasis, including BA synthesis, metabolism, transport, and enterohepatic circulation of BAs. Besides, FXR is involved in regulating diverse physioligical function in both humans and mice. GW4064 is a synthetic FXR agonist which selectively activates FXR and induce the transcription of FXR target genes. In this study, we treated wild type C57BL/6J mice with GW4064 at 100mg per kg body weight or vehicle control. Mice were treated three times, first dose at 8 am, second dose at 6 pm, third dose at 8 am the second day. Mice were sacrificed 2 hours after the last dose, and liver tissues were harvested for analysis. Animal protocols and procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Kansas Medical Center. Total RNA from livers was prepared with TRIzol Reagent (Invitrogen, CA), and the whole transcription expression levels were determined using Mouse Gene 1.0 ST Array system manufactured by Affymetrix, Inc..

2014-07-24 | E-GEOD-57305 | biostudies-arrayexpress

Altered mRNA expression profile of GW4064 treated mouse livers compared to vehicle control

2014-07-24 | GSE57305 | GEO

Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

Project description:Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

| PRJNA891340 | ENA

FXR protects cisplatin-induced AKI via transcriptional regulation of ferroptosis.

Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.

2022-07-06 | GSE193860 | GEO

Analyzing the transcriptomic response of MCF7 breast cancer cells to NR1H4 agonist GW4064

Project description:Computational analysis identified NR1H4 as an active nuclear receptor in a xenograft model of breast cancer. Since there is evidence that NR1H4 agonist, GW4064, reduces MCF7 cell proliferation, here, we wanted understand the transcriptional changes induced by activating this nuclear receptor. We measured changes in gene expression due to GW4064-treatment and applied gene set enrichment analysis to further understand the perturbed molecular pathways.

2019-10-01 | GSE138138 | GEO

Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia.

Project description:Pancreatic acinar cells display a remarkable degree of plasticity and can dedifferentiate into ductal-like progenitor cells by a process known as acinar ductal metaplasia (ADM). ADM is believed to be one of the earliest precursor lesions toward the development of pancreatic ductal adenocarcinoma and maintaining the pancreatic acinar cell phenotype suppresses tumor formation. The effects of a novel pStat3 inhibitor (LLL12B) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) were investigated using 3-D cultures from p48Cre/+ and p48Cre/+LSL-KrasG12D/+ (KC) mice. LLL12B and TSA inhibited ADM in both KC and p48Cre/+ mouse pancreatic organoids. Furthermore, treatment with LLL12B or TSA on dedifferentiated acini from p48Cre/+ and KC mice that had undergone ADM produced morphologic and gene expression changes that suggest a reversal of ADM. Validation experiments using qRT-PCR (p48Cre/+ and KC) and RNA sequencing (KC) of the LLL12B and TSA treated cultures showed that the ADM reversal was more robust for the TSA treatments. Pathway analysis showed that TSA inhibited Spink1 and PI3K/AKT signaling during ADM reversal. The ability of TSA to reverse ADM was also observed in primary human acinar cultures. We report that pStat3 and HDAC inhibition can attenuate ADM in vitro and reverse ADM in the context of wild-type Kras. Our findings suggest that pharmacological inhibition or reversal of pancreatic ADM represents a potential therapeutic strategy for blocking aberrant ductal reprogramming of acinar cells.

| S-EPMC9440259 | biostudies-literature

PHARMACOLOGICAL INHIBITION AND REVERSAL OF PANCREATIC ACINAR DUCTAL METAPLASIA

Project description:Acinar ductal metaplasia (ADM), is believed to be one of the earliest precursor lesions towards the development of pancreatic ductal adenocarcinoma, and maintaining the pancreatic acinar cell phenotype suppresses tumor formation. We report that pStat3 and HDAC inhibition can attenuate ADM in vitro and TSA treatment reverses the dedifferentiated phenotype to one that is more acinar. Our findings suggest that pharmacological inhibition or reversal of pancreatic ADM represents a potential therapeutic strategy for blocking ductal reprogramming of acinar cells.

2022-07-01 | GSE195560 | GEO

Genome wide binding and transcriptome analysis of human FXR in primary human hepatocytes [HTS]

Project description:We report the genome-wide profiling of FXR binding by ChIP-seq from GW4064 or DMSO treated primary human hepatocytes. We reported altered RNA expression profiles in primary human hepatocypes upon GW4064 treatment compared to DMSO control by RNA-seq. We also reported the altered RNA expression profiles in livers from WT C57BL/6J mice upon GW4064 treatment compared to vehicle control.

2014-07-24 | GSE57227 | GEO

Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder.

Project description:Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, which we call a pharmagenic enrichment score (PES), identify individuals with a higher burden of genetic risk, localized in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

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