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).
Observational (n=38)
Do visceral adipose tissue-derived small extracellular vesicles from humans with MASLD alter ER stress and mitochondrial respiration in hepatocytes?
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.
Effect estimate: -64% vs untreated, -69% vs CON-sEV
p-value: p=<0.05
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.
Pafili et al. (Fri,) conducted a observational in Metabolic dysfunction-associated steatotic liver disease (MASLD) (n=38). Visceral adipose tissue-derived small extracellular vesicles (VAT-sEV) from MASH patients vs. Untreated or CON-sEV-treated cells was evaluated on Coupled ADP-stimulated respiration in HepG2 hepatocytes (-64% vs untreated, -69% vs CON-sEV, p=<0.05). 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).