Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Microphysiological Model of Human MASLD Reveals Paradoxical Response to Resmetirom

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic disease with multiple etiologies, stemming from the interplay between local and systemic genetic, diet, and gene-environment interactions. To understand the progression of MASLD in a controlled setting, we utilized a human liver microphysiological system (MPS) to establish a physiologically relevant metabolic baseline and probe how primary human hepatocytes respond to perturbations in insulin, glucose, and free fatty acids (FFAs). Replicate liver MPS were maintained in media with either 200 pM or 800 pM insulin for up to 3 weeks alone and in combination with standard glucose (5.5 mM), hyperglycemia (11 mM glucose), normal (20µM) and elevated FFA (100 µM). Together, hyperinsulinemia along with elevated glucose and FFAs, induces the release of pro-inflammatory chemokines, accumulation of triglycerides, and predisposes hepatocytes to insulin resistance. Treatment with the thyroid receptor ß agonist resmetirom normalizes hepatic fat content and partially rescues insulin sensitivity, but paradoxically induces higher CXCL1 and IL8 expression in male and female donors. In aggregate, our enhanced in vitro MPS model establishes a metabolic baseline and perturbed condition that recapitulates a spectrum of phenotypes observed in MASLD, offering improved quantification and insight into disease progression with relevance to human physiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313774 | GEO | 2025/12/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The Mechanism by which HIF-2a Promotes MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by imbalance of lipid metabolism and autoimmune inflammation. The relationship between Hypoxia-inducible Factor 2α (HIF-2α) and the progression of MASLD has been well-documented. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive. Here, hepatocyte-specific HIF-2α knockout mice were used to identify underlying pathophysiological relevance in MASLD. Through multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines to investigate the molecular mechanism of HIF-2α in MASLD progression. Compared to their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in hepatic steatosis and inflammatory pathway induced by high fat diet (HFD). Furthermore, the HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation and endoplasmic reticulum stress in vitro under FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.These data indicate that HIF-2α acts as a contributing factor to MASLD progression via ATF4 signaling.

2025-12-10 | GSE267155 | GEO

Testing the contribution of FGL1 to the pathogenesis of metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with simple steatosis, which can progress to hepatocellular carcinoma (HCC). The pathogenesis of MASLD alters the secretion of hepatokines such as fibrinogen-like 1 (FGL1), a candidate mediator of liver steatosis and hyperglycemia. To investigate the contribution of FGL1 to liver diseases, we compared wild-type mice to mice with hepatocyte-specific deletion of Fgl1 subjected to a steatosis or HCC experimental protocol. We found that mice deficient for Fgl1 in hepatocytes showed higher levels of plasma glucose, pronounced metabolic alterations and liver injury when fed a western diet compared to their wild-type counterparts. However, both genotypes exhibited a similar lipid deposition in the liver. Similarly, wild type and Fgl1-deficient mice displayed comparable liver alterations during HCC progression. We observed that FGL1 expression was repressed during MASLD progression in mice and human concomitantly with the severity of liver injury. Altogether, these findings suggest that FGL1 is not a major contributor to the pathogenesis of MASLD and HCC.

2025-08-27 | GSE291163 | GEO

Hepatocyte-derived Pumilio1-enriched exosomes inhibit HSC activation by suppressing tropomyosin-4 translation

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease globally. Abnormal crosstalk between hepatocytes and hepatic stellate cells (HSCs) leads to liver fibrosis and aggravates MASLD. We explored the role of the RNA-binding protein Pumilio in this process.

2025-04-27 | GSE295362 | GEO

Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease

Project description:DNA demethylation is regulated by the TET family proteins, whose enzymatic activity requires 2-oxoglutarate (2-OG) and iron that both are elevated in MASLD. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 substantially alleviated MASLD progression. Whole body Knockout of TET1 (TKO) slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, were significantly decreased upon TET1 depletion. Moreover, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.

2025-03-04 | GSE286394 | GEO

Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients [ChIP-seq]

Project description:Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MASLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MASLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MASLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.

2025-08-06 | GSE268361 | GEO

Adipocyte-specific deletion of gp130 prevents ketogenic AQ1 diet–induced hepatic steatosis

Project description:Metabolic dysfunction-associated fatty liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes (T2D), can progress to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. Ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms. Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.

2025-08-07 | GSE294746 | GEO

Induction ofsteatosis in primary human hepatocytes manifests into hepatic pathophysiology of metabolic dysfunction-associated liver disease

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

Targeting Senescent Hepatocytes for Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-organ Dysfunction

Project description:Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.

2025-02-21 | GSE288534 | GEO

Loss of Mtarc1 Protects Against Steatotic Liver Disease in Mice

Project description:Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment. Methods: To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism. Results: Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion. Conclusions: These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.

2026-01-13 | GSE315678 | GEO

Long-acting STK25 antisense oligonucleotide as a therapeutic candidate for MASLD

Project description:Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and a leading cause of liver-related morbidity. Insulin resistance and hepatic lipid metabolism dysfunction are recognized as central pathological mechanisms, yet no therapy is currently approved specifically for MASLD. Antisense oligonucleotides (ASOs) are single-stranded nucleotide drugs with high target specificity and long-lasting activity, making them well suited for chronic metabolic diseases. Here, we describe a novel ASO candidate targeting serine/threonine kinase 25 (STK25), a lipid droplet–associated kinase implicated in MASLD pathogenesis. In three human cell lines, the ASO (c337) robustly reduced STK25 expression. For in vivo validation, we generated Gc337 by GalNAc conjugation to enable liver-specific delivery. In a high-fat diet-induced MASLD mouse model, Gc337 significantly improved insulin sensitivity, reduced hepatic lipid accumulation, and lowered body weight, with efficacy comparable to resmetirom, the only FDA-approved therapy for metabolic-associated steatohepatitis. A single injection sustained >50% hepatic Stk25 knockdown for 35 days without hepatotoxicity, underscoring its long-acting therapeutic profile. Importantly, c337 was designed to avoid all known single-nucleotide polymorphisms (SNPs), ensuring efficacy across genetically diverse populations. Together, these findings establish Gc337 as a durable, SNP-aware, and clinically translatable nucleic acid–based therapeutic candidate for MASLD.

2025-09-28 | GSE308862 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data