Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IPSC-Derived Hepatocytes from Patients with MASLD Exhibit Early Mitochondrial Dysfunction

ABSTRACT: iPSCs from 10 MASLD patients and 10 healthy control subjects genotyped for the I148M variant of PNPLA3 were differentiated to iPSC-Heps. Mitochondrial mass and function were assessed under basal culture conditions and following short-term exposure to exogenous palmitate. Outcomes included gene expression, mitochondrial oxygen consumption, ROS production and cellular energy status. iPSC-Heps from MASLD patients exhibited mitochondrial alterations characteristic of their diseased origin. The degree of mitochondrial dysfunction seen in MASLD iPSC-Heps was reminiscent of that described clinically in early MASLD, prior to progression to steatohepatitis. Mitochondrial alterations in MASLD iPSC-Heps occurred independently of PNPLA3 genotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306392 | GEO | 2026/08/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes

Project description:Genetic variants in lipid metabolism influence the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and end-stage liver disease (ESLD). The mechanisms by which these variants drive disease are poorly understood. Because of the PNPLA3-I148M variant's strong correlation with all stages of the MASLD spectrum and the lack of tractable therapeutic targets, we sought to understand its impact on cellular function and liver metabolism. Primary human hepatocytes (HAH) and iPSC-derived hepatocytes (iHeps) from healthy individuals possessing the PNPLA3-I148M mutation were characterized for changes in lipid metabolism, cellular stress, and survival. Using lipidomics, metabolomics, stable isotope tracing, and flux propensity analysis, we created a comprehensive metabolic profile of the changes associated with the PNPLA3-I148M variant. Functional analysis showed that the presence of the PNPLA3-I148M variant increased endoplasmic reticulum stress, mitochondrial dysfunction, and peroxisomal β-oxidation, ultimately leading to cell death via ferroptosis. Nutritional interventions, ferroptosis-specific inhibitors, and genetic approaches modulating GPX4 activity in PNPLA3-I148M HAH and iHeps decreased programmed cell death. Our findings indicate that therapies targeting ferroptosis in patients carrying the PNPLA3-I148M variant could affect the development of MASLD and ESLD and highlight the utility of iPSC-based models for the study of genetic contributions to hepatic disorders.

2025-11-20 | GSE309786 | GEO

The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics

Project description:Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD to date. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.

2024-04-10 | PXD046335 | Pride

The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics

Project description:Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-drivencellular change.

2024-04-09 | GSE261297 | GEO

RNA-Seq of isolated primary human hepatocytes carrying the PNPLA3-I148M mutation compared to the WT

Project description:Although, there has been strong correlation between PNPLA3-I148M variants and metabolic dysfunction-associated steatotic liver disease (MASLD), the mechanism by which this variant drive the disease is not well understood. To this end, we perform this experiment to understand the transcriptomic changes that can be attributed to this variant. The total RNA was extracted from isolated primary human hepatocytes using RNeasy Plus Micro Kit (Qiagen). The sequencing library was constructed by following the Illumina Nextera XT Sample Preparation Guide. One nanogram of input cDNA was tagmented and amplified using the Illumina Nextera XT kit. Equimolar amounts of each sample were finally pooled and sequenced on an Illumina Nextseq 500 system, using a paired-end 75-bp strategy

2025-10-14 | E-MTAB-15689 | biostudies-arrayexpress

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

Induced Pluripotent Stem Cell Derived Liver Model for the Study of PNPLA3 Associated Non-Alcoholic Fatty Liver Disease

Project description:In order to identify molecular mechanisms associated with PNPLA3 associated non-alcoholic fatty liver disease, we ran RNA sequencing on human induced pluripotent stem cell-derived hepatocyte like cells that were homozygous for the wild type PNPLA3 allele, homozygous for the risk PNPLA3 allele (I148M), or had a complete knock-out of the PNPLA3 gene. The cells were then treated with either oleic acid or palmitic acid to induce a steatotic or a lipotoxic phenotype, respectively. The cells were treated with control medium or medium supplemented with 0.25 mM oleic acid or palmitic acid for 24 hours before samples were collected for RNA sequencing.

2021-09-10 | GSE158182 | GEO

iPSC-Derived Hepatocytes from Patients with MASLD Exhibit Early Mitochondrial Dysfunction

Project description:iPSC-Derived Hepatocytes from Patients with MASLD Exhibit Early Mitochondrial Dysfunction

| PRJNA1310570 | ENA

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

Western Diet induces MASLD and major transcriptional reprogramming in the liver-gut axis of early zebrafish larvae

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition associated with western diet and sedentary lifestyle. Larval zebrafish is widely used as disease model and drug testing platform for liver diseases. Here, it was aimed to generate MASLD model of zebrafish at an early developmental stage of 9 – 12 dpf, by feeding larvae with high fat high cholesterol egg yolk (BEY) or custom designed palmitate, cholesterol and fructose rich, low fiber western diet (WD) and different diets. Diet induced fat accumulation and histopathological changes in gut-liver axis were defined in a time dependent manner. Whole organism level transcriptomic changes were determined with a bulk sequencing approach, that enabled comparison across diets and time points in an affordable manner. Both diets induced an upregulation of lipid/cholesterol transport genetic signatures. Interestingly cholesterol biosynthesis was activated in BEY fed larvae, while it was suppressed in WD-fed larvae. WD diet suppressed lipid synthesis and oxidoreductase activity gene signatures, activated a large network of ribosome biogenesis and translation genes, and suppressed cell cycle in the organism. Cyp7a1 was induced upon egg yolk feeding while it was suppressed in the WD group. WD diet induced lipid droplet formation in the intestinal tissue, as well as structural changes. This study provides an elaborate investigation of western diet induced zebrafish MASLD model by reflecting structural alterations in the liver-gut axis and important gene expression. It features western diet as an effective inducer of early larval MASLD.

2026-09-01 | GSE334507 | GEO

Prime Editing Enables Isogenic Modeling of PNPLA3-I148M-Associated Lipotoxicity in Hepatocytes

Project description:We demonstrate that prime editing enables a precise approach for modeling PNPLA3-I148M in human hepatocytes, offering a platform to investigate genotype-specific cellular responses. By combining precise genome editing with human cell modeling, this study provides new insight into the biology of a key risk allele and establishes a platform for personalized therapeutic strategies targeting genetically defined subgroups of liver disease.

2026-07-01 | GSE313544 | 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