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Transcriptional profiling of liver obtained from a mouse model for metabolic dysfunction-associated steatotic liver disease

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide and closely associated with type 2 diabetes mellitus (T2DM). The pathogenesis of MASLD is multifaceted and its treatment options are very limited. Consequently, it is urgent to identify novel therapeutic targets and develop effective treatment strategies. RNA sequencing analysis was performed to understand the transcriptomic changes in a mouse model of MASLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE279512 | GEO | 2025/01/20

REPOSITORIES: GEO

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A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [RNA-seq]

Project description:The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Considering the fact that MASLD patients accompanying type 2 diabetes mellitus (T2DM) have high risk of developing metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, and HCC, we treated low-dose streptozotocin (STZ; 40 mg/kg) for 5 consecutive days and subsequently fed a high-fat diet (HFD) to male C57BL/6J mice at 7 weeks of age (STZ+HFD). STZ+HFD mice gradually developed fatty liver, MASH, hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. In particular, from 20 weeks of age, MASH was evident, and from 32 weeks of age, advanced fibrosis was developed. At 38 weeks, a proportion of STZ+HFD mice developed HCC, which was subsequently observed in all mice up to 68 weeks of age. Furthermore, the hepatic transcriptomic features of STZ+HFD mice closely reflected those of obese patients with T2DM, MASH and MASLD-related HCC. Notably, dietary changes and tirzepatide administration alleviated MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ+HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients with metabolic dysfunction was successfully established.

2024-06-17 | GSE246221 | GEO

Metabolic dysfunction-associated steatotic liver disease may increase intrahepatic interferon gene signatures in patients with chronic hepatitis B

Project description:As metabolic dysfunction-associated steatotic liver disease (MASLD) frequently co_x0002_occurs in patients with chronic hepatitis B (CHB), the interplay between these two common liver conditions remains largely unexplored. A recent study suggest that MASH comorbidity can reduce intrahepatic interferon pathway activity and macrophage gene signatures in HBeAg_x0002_negative chronic HBV (ENEG) patients, potentially contributing to persistent infection and fibrosis. However, it remains unclear whether this phenomenon also occurs in MASLD with CHB patients.

2025-01-27 | GSE288077 | GEO

multiomics depicting the immunometabolism landscape of steatotic livers undergoing bariatric surgery and diet intervention

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide that encompasses a spectrum of steatosis, inflammation, and fibrosis. Evidence suggests that weight loss approaches such as dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation. However, it remains unclear about the effects of weight loss on the hepatic immune mechanisms in MASLD. Therefore, this study aims to elucidate the intricate immunometabolic landscape of steatotic livers following DI and BS by employing the sleeve gastrectomy (a typical BS procedure) and comparable food intake after sham surgery in a rat model of MASLD. Single-cell (sc) and single-nuclei (sn) transcriptome analysis together with spatial metabolomics and immunohistochemistry were utilized to depict immunometabolic landscape, while circulating markers were assessed in serum. Furthermore, artificial intelligence (AI)-based image analysis was introduced to characterize the distribution of hepatocytes, myeloid cells and lymphocytes.

2024-09-12 | GSE254841 | GEO

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) [MouseMethylation]

Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied DNA methylation changes in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory activation of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

2024-03-01 | GSE238173 | GEO

Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied transcriptome profile changes that could induce changes in DNA methylation in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory transcription of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

2024-03-01 | GSE238201 | GEO

Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver disease [ATAC-seq]

Project description:Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD). To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants. We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue. Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis (Lee et. al, eBioMedicine 2024).

2024-07-11 | GSE269929 | GEO

2024-07-11 | GSE269926 | GEO

ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia/reperfusion injury

Project description:Abstract Background & Aims: In liver transplantation, steatotic donor livers are rapidly increasing but are more susceptible to ischemia-reperfusion (I/R) injury. This study aimed to investigate the underlying mechanisms and identify therapeutic targets. Methods: Cell death markers were determined in donor livers and animal models. Casp8f/f;Alb-Cre, Ripk1D138N/D138N, Tnf-/-, Ripk3-/-, Trif-/-, Zbp1-/- mice were fed high fat diet or choline-deficient high fat diet to induce steatotic livers and were then subjected to I/R injury to investigate the mechanisms of cell death and inflammation. Primary mouse or human hepatocytes were isolated and subjected to hypoxia-reoxygenation challenge to further elucidate the regulation mechanisms. Results: Apoptosis- and inflammation-induced injury was exacerbated in I/R process of steatotic livers, with inflammation-induced injury playing a more predominant role. In both normal and steatotic livers, caspase-8 ablation mitigated I/R injury by reducing apoptosis but not inflammation while RIPK1 kinase inhibition more effectively protected against I/R injury by alleviating both apoptosis and inflammation. Z-DNA binding protein 1 (ZBP1) but not TNF-α deficiency inhibited RIPK1 activation and protected against I/R injury in steatotic livers but not normal livers. In steatotic livers, overmuch palmitic acid triggered ZBP1 transcription through activating JNK pathway. During liver transplantation, excessive reactive oxygen species were generated during I/R injury and triggered ZBP1 oligomerization, which led to the kinase activation of RIPK1 and the subsequent aggravation of apoptosis- and inflammation-induced injury. Conclusions: ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver I/R injury, which could be leveraged to protect steatotic donor livers in transplantation.

2024-06-01 | GSE254747 | GEO

Mettl3-m6A-YTHDF1 axis promotion of mitochondrial dysfunction in metabolic dysfunction–associated steatotic liver disease (MASLD)

Project description:The N6-methyladenosine (m6A) mRNA modification and the mitochondrial respiratory chain (MRC) hold paramount importance in the advancement of MASLD. This study thoroughly investigates the relationship and impact of m6A mRNA modification and mitochondrial function in the progression of MASLD. Here we report that the mRNA and protein levels of mitochondrial respiratory chain (MRC) subunits showed inconsistent trends in vivo experiments. Abnormal m6A modification and mitochondrial dysfunction in MASLD were attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. Mettl3 promoted the MRC's function. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed MRC. In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 complex axis, especially by the role of YTHDF1. Our research has offered a novel perspective on the involvement of m6A mRNA methylation in the pathogenesis of MASLD.

2024-09-20 | PXD047819 | Pride

Aging Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease by Inducing Ferroptotic Stress

Project description:Aging increases the risk for failure of many metabolically-stressed organs and exacerbates liver degeneration related to obesity and diabetes. We used snRNA-seq to identify the effect of metabolic disease (MASLD) on biological aging of hepatocyte.

2024-07-02 | GSE262939 | GEO

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