Fibrogenic gene signature as early prediction for the efficacy of pharmacological interventions for MASH-associated fibrosis, part1
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ABSTRACT:
PROVIDER: PRJNA1226630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32429953_1.fastq.gz | Fastqsanger.gz | |||
| SRR32429953_2.fastq.gz | Fastqsanger.gz | |||
| SRR32429955_1.fastq.gz | Fastqsanger.gz | |||
| SRR32429955_2.fastq.gz | Fastqsanger.gz |
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Project description:Background and aims: The incidence of metabolic dysfunction-associated steatohepatitis (MASH) and associated liver fibrosis is rapidly increasing, while pharmacological treatment options remain limited. Despite great efforts in developing novel MASH therapeutics, many investigative therapeutics that reduced fibrosis in preclinical models ultimately lacked efficacy in clinical trials. Therefore, we explored the possibility to predict the efficacy of investigative therapeutics on fibrogenic drive in the early stages of disease development and before effects on pathology become evident. Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity and MASH. Mice were subsequently treated for four weeks with various therapeutics with established efficacy (obeticholic acid) or lack of efficacy (cenicriviroc, pioglitazone) to study their anti-fibrotic potential. Next, expression of a fibrogenic gene signature was evaluated, which predicts profibrotic processes preceding histopathologic fibrosis. The predictions were validated in parallel with a long-term experiment reaching histological fibrosis endpoints. Results: Cenicriviroc and pioglitazone did not affect HFD-induced fibrosis signature, indicative of no effect of these treatments on active fibrosis processes. Consistently, in the long-term treatment study, both cenicriviroc and pioglitazone did not affect HFD-induced histologically measured fibrosis. In contrast, obeticholic acid improved the early fibrogenic gene signature indicating a less fibrotic state compared with untreated HFD controls. These early gene expression changes aligned with long-term histological fibrosis endpoints and clinical data on these investigative therapeutics. Conclusions: This study highlights the potential of using short-term studies and applying a fibrogenic gene signature as an early screening tool to investigate the efficacy of investigative drugs on MASH-associated fibrosis. This signature, which is based on the active fibrosis processes in humans, may allow rapid screening of therapeutics and their combinations in translational mouse models to save time and resources.
2025-06-18 | GSE290235 | GEO
Project description:Background and aims: The incidence of metabolic dysfunction-associated steatohepatitis (MASH) and associated liver fibrosis is rapidly increasing, while pharmacological treatment options remain limited. Despite great efforts in developing novel MASH therapeutics, many investigative therapeutics that reduced fibrosis in preclinical models ultimately lacked efficacy in clinical trials. Therefore, we explored the possibility to predict the efficacy of investigative therapeutics on fibrogenic drive in the early stages of disease development and before effects on pathology become evident. Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity and MASH. Mice were subsequently treated for four weeks with various therapeutics with established efficacy (obeticholic acid) or lack of efficacy (cenicriviroc, pioglitazone) to study their anti-fibrotic potential. Next, expression of a fibrogenic gene signature was evaluated, which predicts profibrotic processes preceding histopathologic fibrosis. The predictions were validated in parallel with a long-term experiment reaching histological fibrosis endpoints. Results: Cenicriviroc and pioglitazone did not affect HFD-induced fibrosis signature, indicative of no effect of these treatments on active fibrosis processes. Consistently, in the long-term treatment study, both cenicriviroc and pioglitazone did not affect HFD-induced histologically measured fibrosis. In contrast, obeticholic acid improved the early fibrogenic gene signature indicating a less fibrotic state compared with untreated HFD controls. These early gene expression changes aligned with long-term histological fibrosis endpoints and clinical data on these investigative therapeutics. Conclusions: This study highlights the potential of using short-term studies and applying a fibrogenic gene signature as an early screening tool to investigate the efficacy of investigative drugs on MASH-associated fibrosis. This signature, which is based on the active fibrosis processes in humans, may allow rapid screening of therapeutics and their combinations in translational mouse models to save time and resources.
2025-06-18 | GSE290237 | GEO
Project description:Fibrogenic gene signature as early prediction for the efficacy of pharmacological interventions for MASH-associated fibrosis, part2
| PRJNA1226631 | ENA
Project description:Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show here that human fibrotic MASH livers have decreased EHBP1, a novel GWAS locus associated with LDL cholesterol, and that the EHBP1 rs10496099 T>C variant in MASH patients is associated with decreased hepatic EHBP1 expression and with augmented MASH fibrosis. Congruent with the human data, EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin (SORT1)-mediated PCSK9 secretion, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects intracellular localization of retromer, a protein complex required for sortilin stabilization. Our novel therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the TNFα/PPARα pathway suppresses EHBP1 in MASH. These data not only provide new mechanistic insight into the role of EHBP1 in cholesterol metabolism and MASH fibrosis by uncovering the interaction between EHBP1 and other cholesterol-related loci, including SORT1, PCSK9, and LDLR, but also elucidate a novel interplay between inflammation and EHBP1-mediated cholesterol metabolism.
2025-01-23 | GSE232780 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) represents a significant and growing public health concern worldwide, characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis. In vitro models of NASH play a crucial role in elucidating the underlying mechanisms of disease pathogenesis, identifying potential therapeutic targets, and evaluating the efficacy of pharmacological interventions. Several preclinical models of MASH have been developed and are being used extensively to study these areas. While standard cell culture models allow for elucidation of certain molecular pathways involved in MASH pathogenesis, they lack three-dimensional architecture and cellular heterogeneity observed in native liver tissue, potentially limiting their physiological relevance and inability to fully capture the multifactorial nature of the disease Precision cut liver slices from MASH livers retain the complex multicellular architecture of the liver including hepatocyte arrangement, sinusoidal structure, and cellular interactions, but the metabolism deteriorates over a short period of time (usually reported as 2 days). Human liver organoids from iPSCs (induced pluripotent stem cells) retain the genetics of the patients but fail to fully differentiate into hepatocytes or have the liver architecture. Human liver spheroids incubated in a MASH cocktail develop several phenotypic characteristics of a MASH liver, but the small spheroid size precludes extensive histological comparisons to MASH livers. Microphysiological systems (MPS) or “liver on a chip” in which 3D cultures are perfused, maintain many of the physiological functions of the liver owing to precise control over microenvironmental parameters, including fluid flow, nutrient gradients, and mechanical cues. However, MPS are difficult to scale up and have not been developed to reproduce a MASH phenotype. In comparison, bioprinted liver tissues for MASH have many advantages. Organovo’s 3D bioprinted liver tissues are comprised of all major primary liver cells including hepatocytes, endothelial cells, stellates and Kupffer cells, mixed in physiologically relevant ratios. These cells are then bioprinted in precise pre-defined liver specific geometries to recapitulate complexity of the hepatic microenvironment.. This mimicking of tissue architecture enables more accurate representation of cellular interactions, spatial organization, and microenvironmental cues crucial for MASH pathogenesis. The liver tissues developed using this method maintain differentiation and metabolism over several weeks. In this paper, we further demonstrated that upon treatment with a MASH induction cocktail, these liver tissues respond accurately by developing steatosis and fibrosis Tissue response varies depending in response to the complexity of the MASH cocktail.
2024-11-29 | GSE280378 | GEO
Project description:PART1 was knocked down down using GapmeRs specific to PART1. The breast cancer cells used in this study were confirmed to have PART1 expression by qPCR and knockdown of PART was confirmed by qPCR.
2021-02-28 | GSE156114 | GEO
Project description:The expression of lncRNA PART1 was found to be significantly upregulated in platinum-sensitive patients with ovarian cancer, and this upregulation was positively correlated with a favorable prognosis. Cellular experiments demonstrated that inhibition of PART1 led to cellular senescence and increased resistance to cisplatin and PARP inhibitors. Thus, LncRNA PART1 is a novel target for overcoming resistance to PARP inhibitors in ovarian cancer.
2024-02-01 | GSE253450 | GEO
Project description:PART1 was knocked down down using GapmeRs specific to PART1. The breast cancer cells used in this study were confirmed to have PART1 expression by qPCR and knockdown of PART was confirmed by qPCR.
2021-02-28 | GSE163569 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.
2025-05-13 | GSE295343 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. We report that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator activated receptor-alpha (PPARα) transcription and fatty acid β-oxidation (FAO), and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, blocking oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lower steatosis, inflammation, and fibrosis by inducing PPARα-driven FAO, and suppressing monocyte chemotaxis, nuclear factor-kappaB and transforming growth factor-beta targets. These findings highlight hepatic oxalate overproduction as a new target for the treatment of MASH.
2024-08-07 | GSE265985 | GEO