What is the clinical evidence from this study?

Study design: Observational. Population: Metabolic dysfunction-associated steatotic liver disease (MASLD) (n=38). Intervention: Visceral adipose tissue-derived small extracellular vesicles (VAT-sEV) from MASH patients vs. Untreated or CON-sEV-treated cells. Primary outcome: Coupled ADP-stimulated respiration in HepG2 hepatocytes (-64% vs untreated, -69% vs CON-sEV, p=<0.05).

What does this research mean for the field?

Visceral adipose tissue-derived small extracellular vesicles are increased in humans with metabolic dysfunction-associated steatotic liver disease (MASLD) and may fuel disease progression by reducing mitochondrial respiration and activating endoplasmic reticulum stress in hepatocytes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aims to examine the relationship between visceral adipose tissue-derived small extracellular vesicles and liver metabolism in the context of metabolic dysfunction-associated steatotic liver disease.

June 7, 2026

2653-P: Visceral Adipose Tissue–Derived Small Extracellular Vesicles from Humans with MASLD Alter ER Stress and Mitochondrial Respiration in Hepatocytes

Q: What are the key findings of this study?

VAT-derived sEVs from individuals with MASH decreased coupled ADP-stimulated respiration in hepatocytes by 64% versus untreated cells and 69% versus control-sEV-treated cells (p<0.05).

Q: What question did this study set out to answer?

The study aims to examine the relationship between visceral adipose tissue-derived small extracellular vesicles and liver metabolism in the context of metabolic dysfunction-associated steatotic liver disease.

Key Result

VAT-derived sEVs from individuals with MASH decreased coupled ADP-stimulated respiration in hepatocytes by 64% versus untreated cells and 69% versus control-sEV-treated cells (p<0.05).

Key Points

The study aims to examine the relationship between visceral adipose tissue-derived small extracellular vesicles and liver metabolism in the context of metabolic dysfunction-associated steatotic liver disease.
Obtained visceral adipose tissue and liver biopsies from individuals undergoing bariatric surgery, stratified into control, steatosis, and steatohepatitis groups.
Cultured adipose tissue explants to isolate VAT-derived small extracellular vesicles.
Evaluated mitochondrial respiration and ER stress in HepG2 hepatocytes treated with VAT-derived small extracellular vesicles.
Adipo-IR was 5.7-fold higher in metabolic-dysfunction-associated steatohepatitis vs control (p<0.05).
Increased VAT-derived small extracellular vesicles were observed in MASH, with a 1.8- and 2.2-fold increase compared to control and steatosis groups, respectively (both p<0.05).
MASH small extracellular vesicle-treated HepG2 cells showed a 64% decrease in coupled ADP-stimulated respiration compared to untreated, and 69% compared to control-sEV-treated cells (both p<0.05).

Study Design

Type

Observational (n=38)

Structured PICO

Do visceral adipose tissue-derived small extracellular vesicles from humans with MASLD alter ER stress and mitochondrial respiration in hepatocytes?

Population

38 individuals undergoing bariatric surgery, stratified into control, steatosis, and MASH by liver histology, whose visceral adipose tissue was used for ex vivo experiments.

Exposure

Treatment of HepG2 hepatocytes with visceral adipose tissue-derived small extracellular vesicles (VAT-sEV) from individuals with MASLD (MASL or MASH)

Comparator

Untreated HepG2 cells and cells treated with VAT-sEV from control individuals

Outcome

Mitochondrial respiration and endoplasmic-reticulum (ER) stress in HepG2 hepatocytes evaluated by high resolution respirometry and immunoblottingsurrogate

Visceral adipose tissue-derived small extracellular vesicles are increased in humans with MASH and can directly induce ER stress and impair mitochondrial respiration in hepatocytes, potentially driving MASLD progression.

Main Result

Effect estimate: -64% vs untreated, -69% vs CON-sEV

p-value: p=<0.05

Abstract

Introduction and Objective: Increased secretion of small extracellular vesicles (sEV) from subcutaneous adipose tissue (SAT) has been related to metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. However, dysfunctional visceral adipose tissue (VAT), rather than SAT, is the hallmark of insulin resistance (IR) and contributes to MASLD through mechanisms beyond lipid release. We investigate whether the number and cargo of VAT-derived sEV associate with MASLD severity and affect hepatocellular metabolism. Methods: VAT and liver biopsies were obtained from individuals undergoing bariatric surgery, stratified as control (CON; n=12, 40±12 years, BMI 44±6 kg/m2), steatosis (MASL; n=13, 41±8 years, BMI 47±7 kg/m2) and metabolic-dysfunction-associated steatohepatitis (MASH; n=13, 40±11 years, BMI 46±4 kg/m2) by liver histology. Adipose IR was assessed from the Adipo-IR index. VAT-explants were cultured for 48 h and VAT-sEV were isolated via differential centrifugation. Effects of VAT-sEV on mitochondrial respiration and endoplasmic-reticulum (ER) stress in HepG2 hepatocytes were evaluated by high resolution respirometry and immunoblotting. Results: Adipo-IR was 5.7-fold higher in MASH vs CON (p0.05; MASL vs CON p=0.40). MASH featured 1.8- and 2.2-fold more VAT-sEV than CON and MASL, respectively (both p0.05). VAT-sEV from pooled MASLD (MASL+MASH) increased activated eukaryotic initiation factor 2α vs untreated and CON-sEV-treated HepG2 cells (+32% and +47%; both p0.05); HepG2 cells treated with MASH VAT-sEV showed a similar trend (p=0.09 and p=0.06, respectively). Only MASH-sEV-treated HepG2 cells decreased coupled ADP-stimulated respiration vs untreated (-64%, p0.05) and CON-sEV-treated cells (-69%, p0.05). Conclusion: These data provide evidence for increased VAT-derived sEV in MASLD humans, which may reduce mitochondrial respiration, but activate hepatocellular ER stress, potentially fuelling MASLD progression. Disclosure K. Pafili: None. L. Mastrototaro: None. P. Schrauwen: Consultant; Current; AstraZeneca. Research Support; Ended; Pfizer Inc., MedImmune. A. Yavas: None. S. Yilmaz: None. S. Lehr: None. S. Hartwig: None. P. Lipaeva: None. M. Huttasch: None. J. Pützer: None. I. Esposito: None. M. Schlensak: None. F.A. Granderath: None. H. Al-Hasani: None. S. Kahl: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. Funding The research of KP is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): Project number 493659010 in the context of the Clinician Scientist Program (FUTURE-4-CSPMM) and by grants from the German Diabetes Research (DZD) foundation and the Heinrich-Heine-University Düsseldorf.

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