Aldehydes alter TGF-β signaling and induce obesity and cancer
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE273561 | GEO | 2024/08/06
REPOSITORIES: GEO
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Project description:Reliable non-invasive tools to diagnose at risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high risk MASH patients (NAFLD Activity Score (NAS) >4 and fibrosis score >2). In this three-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease (MASLD), we first developed a multi-protein predictor for discriminating NAS>4 based on SOMAscan proteomics quantifying 1,305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N=168), and enhanced by adding clinical variables to create the 9-feature MASH Dx Score which predicted MASH and also high risk MASH (F2+). The MASH Dx Score was validated in two independent, external cohorts from Germany (N=139) and Brazil (N=177). The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of four proteins (THBS2, GDF15, SELE, IGFBP7) was verified by ELISA in the expanded discovery and independently in the two external cohorts. MASH Dx Score incorporated these proteins with established MASH risk factors (age, BMI, ALT, diabetes, hypertension) to achieve good discrimination between MASH and MASLD without MASH (AUC:0.87- discovery; 0.83- pooled external validation cohorts), with similar performance when evaluating high risk MASH F2-4 (vs. MASH F0-1 and MASLD without MASH). The MASH Dx Score offers the first reliable non-invasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high risk MASH in patient cohorts from the US, Brasil and Europe.
2023-12-22 | GSE251855 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275576 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275575 | GEO
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
Project description:Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from steatosis (Metabolic dysfunction-associated steatotic liver, MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. Here we compared gene expression and chromatin accessibility profiles of human HSCs in NORMAL, MASL, and MASH livers at single cell resolution. Methods: 18 human livers were profiled using single-nucleus (sn) RNA-seq and snATAC-seq. High priority targets were identified and then tested in 2D human HSCs, 3D human liver spheroids, and HSC-specific gene knockout mice. Results: This study identified novel gene regulatory mechanisms underlying MASL- and MASH-associated HSC heterogeneity and outlined potential strategies for anti-fibrotic therapy. Specifically, MASH-enriched HSC-subcluster hA1, represented by highly fibrogenic population of myofibroblasts, served as a critical source of extracellular matrix protein (ECM) in MASH, and its activation was regulated via a cross-talk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors (TFs). Additionally, we identified a set of core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive ECM production in hA1 HSCs. The pathological relevance of the selected hA1 targets, such as SERPINE1 and others, was demonstrated using siRNA-based HSC-specific gene knockdown or pharmacological inhibitor of SERPINE1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice with MASH. Conclusion: We identified potential targets for anti-fibrotic therapy of MASH in patients.
2024-11-13 | GSE244832 | GEO
Project description:Background: Biomarkers for metabolic dysfunction-associated steatohepatitis (MASH) have been considered based on proteomic and lipidomic data from plasma and liver tissue without clinical benefits. This study evaluated proteomics-based plasma and liver tissue biomarkers collected simultaneously from patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
Methods: Liver tissue samples and plasma samples were collected during liver biopsy for diagnosis. Untargeted proteomics was performed on 64 patients with MASLD.
Results: Twenty plasma proteins were up or downregulated in patients with MASH compared with those without MASH. The biomarkers utilizing the best combinations of these plasma proteins had an area under the receiver operating curve (AUROC) of 0.671 for detecting those with MASH compared with those without it. However, none of the 20 plasma proteins were represented among the significantly regulated liver tissue proteins in patients with MASH. Ten of them displayed a trend and relevance in liver tissue with MASLD progression. These ten plasma proteins had an AUROC of 0.793 for MASH identification and higher positive and negative predictive values.
Conclusion: The plasma and liver protein expressions of patients with MASH were not directly comparable. Plasma protein biomarkers that are also expressed in liver tissue can help improve MASH detection.
2024-06-07 | MSV000094959 | MassIVE
Project description:Background & Aims:The prevalence of metabolic dysfunction-associated liver disease (MASLD) has been strongly increasing over the last decades. As MASLD is often associated with more severe disease states, such as metabolic dysfunction-associated steato-hepatitis (MASH), insulin resistance and type 2 diabetes, the increasing number of patients will contribute to an epidemic rise in metabolic abnormalities and end stage liver diseases. Despite the high demand, there are still no FDA-approved pharmaceutical treatments for MASLD due to low efficacy and high toxicity of the targets pursued, indicating a lack of appropriate pre-clinical models for selection and validation. To facilitate earlier stop-go decisions for continued target development, we have established and extensively characterized a primary human steatoticin vitrohepatocyte model system that could guide treatment strategies for MASLD. Methods:Cryopreserved primary human hepatocytes of different donors varying in sex and ethnicity were cultured with free fatty acids (FFA) in a 3D collagen sandwich system for 7 days and the development of MASLD was followed by assessing classical hepatocellular functions. As aproof-of-concept, the effects of Firsocostat (GS-0976) onin vitroMASLD phenotypes were evaluated. Results:Incubation with FFA induced known MASLD pathologies, including steatosis, insulin resistance, mitochondrial dysfunction, inflammation and alterations in prominent human gene signatures similar to patients with MASLD/MASH, indicating the recapitulation of human MASLD in this system. As the application of Firsocostat rescued clinically observed fatty liver disease pathologies, it highlights the ability of thein vitrosystem to test drug efficacy and potentially characterize their mode of action. Conclusions:Altogether, our human MASLDin vitromodel system could guide the development and validation of novel targets and drugs for the treatment of MASLD.
2024-08-30 | GSE247407 | GEO
Project description:The burden of senescent hepatocytes correlates with MASLD severity but mechanisms driving senescence, and how it exacerbates MASLD are poorly understood. Hepatocytes become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine if the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA seq analysis confirmed that hepatocyte populations of MASLD livers are depleted of Smo(+) cells and enriched with senescent cells. When fed CDA-HFD, Smo(-) mice had lower antioxidant markers and developed worse DNA damage, senescence, MASH and liver fibrosis than Smo(+) mice. Sera and hepatocyte-conditioned medium from Smo(-) mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo(-) hepatocytes with TP reduced senescence and lipotoxicity; inhibiting TP in Smo(+) hepatocytes had the opposite effects and exacerbated hepatocyte senescence, MASH, and fibrosis in CDA-HFD-fed mice.Therefore, we found that inhibiting Hedgehog signaling in hepatocytes promotes MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.
2024-10-01 | GSE273523 | GEO
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
Project description:With domain focused CRISPR screen, we revealed Fanconi anemia (FA) proteins UBE2T (an E2) and FANCL (an E3) as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxic effects of endogenous aldehydes. We provide evidence that DNA hypermethylation and transcriptional silencing of ALDH2 occur in a recurrent manner in human AML patient samples, which is sufficient to confer FA pathway dependency in this disease. Taken together, our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.
2021-03-25 | GSE169586 | GEO