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Sex- and age-associated factors drive the pathophysiology of MASLD

ABSTRACT: Sex- and age-associated factors drive the pathophysiology of MASLD

PROVIDER: PRJNA1148454 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30252130_1.fastq.gz	Fastqsanger.gz
	SRR30252130_2.fastq.gz	Fastqsanger.gz
	SRR30252131_1.fastq.gz	Fastqsanger.gz
	SRR30252131_2.fastq.gz	Fastqsanger.gz
	SRR30252132_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Sex- and age-associated factors drive the pathophysiology of MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex- and age-associated mechanisms underlying the pathophysiology remain poorly understood. Here we show distinct responses to a HFD between males and females. Our study underscores the need for utilizing both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals. Hepatology Communications 2024

2024-09-03 | GSE274914 | GEO

Effects of D4-MASLD and D5-MASLD Diets on Rats: Pathway Alterations Similar to Human MASLD

Project description:Animal models are essential to understand the mechanisms underlying the onset and progression of metabolic associated steatotic liver disease (MASLD), a rapidly growing form of chronic liver disease driven largely by the global rise in metabolic syndrome. However, existing animal models for MASLD often fail to accurately reproduce advanced human liver disease, and have varying degrees of clinical relevance. To address this, we have undertaken efforts to create a dietary translational model of MASLD in rats that closely replicates the full MASLD phenotype observed in humans, including advanced fibrosis, portal hypertension, and metabolic syndrome. Three MASLD rat models were developed by sequentially combining a high-fat glucose-fructose diet (HFGFD) with additional factors: lipopolysaccharide, increased cholesterol (Chol), and cholic acid (CA) at different concentrations. Of these, two diets—D4-MASLD (HFGFD + 2% Chol) and D5-MASLD (HFGFD + 2% Chol + 0.1% CA)—effectively replicated MASLD characteristics. Transcriptomic analysis revealed that while both diets significantly altered gene expression compared to controls, D5-MASLD had a greater impact on the activation of inflammation and immune response pathways. The inclusion of CA in D5-MASLD exacerbated pathways related to microbiota changes, intestinal barrier dysfunction, and bacterial translocation. Additionally, comparison of the transcriptomic profiles of these diet-induced rat models with data from MASLD/MASH patients further validated the relevance of these models, establishing a robust platform for studying MASLD pathogenesis and evaluating potential therapeutic interventions.

2026-04-20 | GSE282001 | GEO

The Senescence-associated Secretome of Hedgehog-deficient Hepatocytes Drives MASLD Progression

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

The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents progression of MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD, however, the role of the Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1, unexpectedly, promotes hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.

2026-03-26 | PXD072418 | Pride

Intestinal organoid expression data from patients with MASLD-cirrhosis versus non-fibrotic MASLD

Project description:This study aimed to establish and characterize an in vitro model of human intestinal organoids isolated from duodenal samples of patients with non-fibrotic MASLD and those with MASLD-cirrhosis. Whole transcriptome analysis and the energetic and redox status of the organoids were assessed to characterize intestinal functional impairment in the context of MASLD. We used microarrays to detail the whole transcriptome dysregulation underlying intestinal dysfunction in organoids isolated from chirrotic versus non-fibrotic MASLD patients.

2025-09-04 | GSE299719 | GEO

Gene expression profile at single cell level of hepatocytes and non parenchymal cells (NPCs) isolated from a murine model of MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) embraces different conditions, including metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The landscape of cellular abnormalities occurring in the different stages of MASLD as well as the processes which drive MASLD evolution are not completely clarified. We used single cell RNAsequencing (scRNAseq) to unravel cellular heterogeneity affecting livers during the switching from simple steatosis towads MASH and and MASH-fibrosis.

2025-02-28 | GSE284186 | GEO

Mitochondrial dysfunction charachterizes the multigenerational effects of maternal obesity on MASLD

Project description:Although maternal obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the pathogenesis remains unclear. We aimed to evaluate the effect and mechanisms of multigenerational maternal western diet (WD) on MASLD progression, and test drug candidates in a preclinical model. Female mice were fed WD from 8 weeks before breeding initiation with a normal chow (NC)-fed male, throughout pregnancy and lactation. Male offspring were weaned onto NC or WD and assessed at the age of 16 weeks. Maternal WD feeding aggravated body weight gain, insulin resistance, steatosis and inflammation. Fibrosis was only observed in offspring exposed to maternal WD. Mechanistically, the latter exhibited reduced OXPHOS activity. Maternal WD aggravates MASLD in male offspring, with mitochondrial dysfunction contributing to disease severity.

2025-06-18 | GSE291363 | GEO

Effects of D4-MASLD and D5-MASLD Diets on Rats: Pathway Alterations Similar to Human MASLD

Project description:Effects of D4-MASLD and D5-MASLD Diets on Rats: Pathway Alterations Similar to Human MASLD

| PRJNA1186599 | ENA

Impact of Age and Sex on Plasma Proteome Changes in Mice upon Radiation Exposure

Project description:The aim of this project is to assess the impact that age and sex have as parameters for biomarker discovery in radiation research using high-throughput proteomics.

2022-05-10 | PXD015859 | Pride

Age-, sex- and proximal–distal-resolved multi-omics identifies regulators of intestinal aging in non-human primates

Project description:To determine the molecular landscape of large intestinal aging, we collected 104 pieces of fresh large intestinal tissue from 26 Macaca fascicularis and performed age-, location-, and sex-resolved multi-omics analyses, including transcriptomics, proteomics, phosphoproteomics and metabolomics.

2024-01-18 | PXD039361 |

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