Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr−/−.Leiden mice
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PROVIDER: PRJNA862369 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR20648916_1.fastq.gz | Fastqsanger.gz | |||
| SRR20648916_2.fastq.gz | Fastqsanger.gz | |||
| SRR20648917_1.fastq.gz | Fastqsanger.gz | |||
| SRR20648917_2.fastq.gz | Fastqsanger.gz | |||
| SRR20648918_1.fastq.gz | Fastqsanger.gz |
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Project description:Title: White adipose tissue inflammation and gut permeability develop prior to NASH development, associated with increased oxidative stress, intrahepatic diacylglycerol and proinflammatory chemokines in the liver of diet-induced obese and hyperinsulinemic Ldlr-/-.Leiden mice Abstract: NAFLD progression from simple steatosis to NASH and fibrosis is driven by an intricate interplay between molecular and cellular mechanisms. These drivers are not limited to the liver itself but also white adipose tissue and gut may contribute. Current knowledge on these drivers is mostly based on studies that investigate these at a single time point (typically end-stage disease). However, such studies provide no insight into the temporal dynamics and chronology, which therefore remain poorly understood. Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity-associated NAFLD and compared to lean controls fed chow. Groups of mice were sacrificed after 8, 16, 28 and 38 weeks to study liver, white adipose tissue, gut and circulating factors to investigate the sequence of pathogenic events in these critical metabolically active organs as well as organ-crosstalk during NAFLD development. Ldlr-/-.Leiden mice on a HFD develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NASH patients, in this translational context WAT and gut dysfunction precede the development of NASH and liver fibrosis.
2023-03-20 | GSE209762 | GEO
Project description:Abstract. Background and aims: Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for treatment of obesity as well. Semaglutide is also postulated to be a promising candidate for treatment of non-alcoholic steatohepatitis (NASH). Here, we evaluated the effects of semaglutide in a translational diet-induced model with advanced NASH and fibrosis. Methods: Ldlr-/-.Leiden mice received a fast food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneously injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined and hepatic transcriptome analysis was performed. Results: In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p<0.001), inflammation (-73%, p<0.001) and completely abolished microvesicular steatosis (-100%, p<0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p<0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Conclusions: Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for treatment of hepatic steatosis and inflammation, while for reversal of advanced fibrosis, combinations with other NASH agents may be necessary.
2023-08-01 | GSE226496 | GEO
Project description:- Background: Obesity in mid-adulthood has been suggested to promote brain aging and is associated with progressive cognitive impairment later in life. However, the structural and functional alterations that underlie obesity-related cognitive dysfunction are still poorly understood, partly owing to the lack of translational models replicating age- and obesity-related brain pathology. - Methods: The effect of age and high-fat diet (HFD)-induced obesity was investigated in adult Ldlr-/-.Leiden mice, an established translational model for obesity and its comorbidities. During mid-adulthood, from three to eight months of age, brain structure and function (hippocampal volume, cortical thickness, white matter integrity, cerebral blood flow (CBF), resting-state functional connectivity) were monitored with brain magnetic resonance imaging, and cognitive function was evaluated using cognitive tests. Brain pathology was further examined with histopathological and gene expression analyses. - Results: Ldlr-/-.Leiden mice showed age-related decreases in cortical thickness, CBF, brain connectivity, and neurogenesis along with the development of neuroinflammation and (short-term) memory impairments. On HFD feeding, Ldlr-/-.Leiden mice exhibited similar features, but memory deficits started at a younger age than in chow-fed mice. HFD-fed mice additionally showed a rise in CBF with concomitant decline in fractional anisotropy in white matter tracts. Analyses of hippocampal gene expression further revealed an age-related suppression of processes related to metabolic and neuronal function while HFD feeding strongly activated neuroinflammatory pathways. - Conclusions: Ldlr-/-.Leiden mice show similar critical age-related changes in brain structure and function as observed in humans. In this mouse model, HFD feeding particularly trigger disturbances in brain blood perfusion and white matter tract integrity, which may underlie an accelerated cognitive decline in obesity.
2025-04-30 | GSE294054 | GEO
Project description:Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.
2022-09-19 | GSE195614 | GEO
Project description:Abstract Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking. In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology. We show that Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed controls, indicating an altered overall microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD affected multiple molecular pathways: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent. This study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.
2023-06-18 | GSE234425 | GEO
Project description:BackgroundNAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood.MethodsHigh-fat-diet (HFD)-fed Ldlr-/-.Leiden mice were compared to chow-fed controls. At t = 0, 8, 16, 28 and 38w mice were euthanized, and liver, WAT depots and gut were analyzed biochemically, histologically and by lipidomics and transcriptomics together with circulating factors to investigate the sequence of pathogenic events and organ cross-talk during NAFLD development.ResultsHFD-induced obesity was associated with an increase in visceral fat, plasma lipids and hyperinsulinemia at t = 8w, along with increased liver steatosis and circulating liver damage biomarkers. In parallel, upstream regulator analysis predicted that lipid catabolism regulators were deactivated and lipid synthesis regulators were activated. Subsequently, hepatocyte hypertrophy, oxidative stress and hepatic inflammation developed. Hepatic collagen accumulated from t = 16 w and became pronounced at t = 28-38 w. Epididymal WAT was maximally hypertrophic from t = 8 w, which coincided with inflammation development. Mesenteric and subcutaneous WAT hypertrophy developed slower and did not appear to reach a maximum, with minimal inflammation. In gut, HFD significantly increased permeability, induced a shift in microbiota composition from t = 8 w and changed circulating gut-derived metabolites.ConclusionHFD-fed Ldlr-/-.Leiden mice develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NAFLD patients, underlining their translational value. We demonstrate that marked epididymal-WAT inflammation, and gut permeability and dysbiosis precede the development of NAFLD stressing the importance of a multiple-organ approach in the prevention and treatment of NAFLD.
| S-EPMC10006542 | biostudies-literature
Project description:- Background: Fibroblast growth factor 21 (FGF21) is considered a promising target for treatment of obesity-associated metabolic diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. Here, we evaluated the effects of a humanized bispecific anti-FGFR1/KLB agonist antibody (bFKB1) that specifically targets FGFR1c and β-klotho, in a translational preclinical model that develops MASH and atherosclerosis. - Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) for 20 weeks, after which mice were treated with an isotype control antibody or bFKB1 for 12 weeks. Effects on pre-existent MASH and atherosclerosis were assessed histopathologically and biochemically. Underlying mechanisms of bFKB1 treatment were investigated by hepatic transcriptomics analysis (NGS). Results: bFKB1 lowered body weight and adipose tissue mass without reducing food intake. bFKB1 intervention reduced plasma insulin, cholesterol, triglycerides, ALT and liver weight. liver steatosis, inflammation and NAS score were significantly lowered. Histological measurement of fibrosis was not significantly affected by the treatment, but new collagen formation was significantly inhibited by bFKB1. Correspondingly, hepatic inflammatory and profibrotic transcriptional programs were broadly inactivated by the treatment. In epididymal white adipose tissue, bFKB1 intervention reduced adipocyte size and inflammation and induced browning, signified by increased UCP1 expression. In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area, that could be attributed to a reduction In severe type V lesions. - Conclusion: The bispecific anti-FGFR1/KLB agonist antibody bFKB1 has strong beneficial metabolic effects in HFD-fed Ldlr-/-.Leiden mice that are associated with a reduction in liver steatosis, inflammation and atherosclerosis. Liver fibrosis was not affected, yet analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration, consistent with a recent clinical study using a FGF21 mimetic.
2025-01-01 | GSE255321 | GEO
Project description:SUMMARY: This article presents a predictive molecular signature that marks the early onset of fibrosis in a translational nonalcoholic steatohepatitis mouse model. Overlap of genes and processes with human nonalcoholic steatohepatitis and a list of top candidate biomarkers for early fibrosis are described. BACKGROUND & AIMS: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. METHODS: A time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. RESULTS: High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. CONCLUSIONS: An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames. Keywords: Systems Biology; Metabolic Syndrome; Liver Disease; Diagnosis.
2018-01-19 | GSE109345 | GEO
Project description:Semaglutide has beneficial effects on non-alcoholic steatohepatitis in Ldlr-/-.Leiden mice
| PRJNA940436 | ENA
Project description:Introduction: It is generally accepted that metabolic inflammation in the liver is an important driver of disease progression in NASH and associated matrix remodeling/fibrosis. However, the exact molecular inflammatory mechanisms are poorly defined in human studies. Investigation of key pathogenic mechanisms requires the use of pre-clinical models, for instance for time-resolved studies. Such models must reflect molecular disease processes of importance in patients. Herein we characterized inflammation in NASH patients on the molecular level by transcriptomics and investigated whether key human disease pathways can be recapitulated experimentally in Ldlr-/-.Leiden mice, an established pre-clinical model of NASH. Methods: Human molecular inflammatory processes were defined using a publicly available NASH gene expression profiling dataset (GSE48452) allowing the comparison of biopsy-confirmed NASH patients with normal controls. Gene profiling data from high-fat diet (HFD)-fed Ldlr-/-.Leiden mice (GSE109345) were used for assessment of the translational value of these mice. Results: In human NASH livers, we observed regulation of 65 canonical pathways of which the majority was involved in inflammation (32%), lipid metabolism (16%), and extracellular matrix/remodeling (12%). A similar distribution of pathways across these categories, inflammation (36%), lipid metabolism (24%) and extracellular matrix/remodeling (8%) was observed in HFD-fed Ldlr-/-.Leiden mice. Detailed evaluation of these pathways revealed that a substantial proportion (11 out of 13) of human NASH inflammatory pathways was recapitulated in Ldlr-/-.Leiden mice. Furthermore, the activation state of identified master regulators of inflammation (i.e., specific transcription factors, cytokines, and growth factors) in human NASH was largely reflected in Ldlr-/-.Leiden mice, further substantiating its translational value. Conclusion: Human NASH is characterized by upregulation of specific inflammatory processes (e.g., "Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes," "PI3K signaling in B Lymphocytes") and master regulators (e.g., TNF, CSF2, TGFB1). The majority of these processes and regulators are modulated in the same direction in Ldlr-/-.Leiden mice fed HFD with a human-like macronutrient composition, thus demonstrating that specific experimental conditions recapitulate human disease on the molecular level of disease pathways and upstream/master regulators.
| S-EPMC5829089 | biostudies-literature