Mitochondrial Dysfunction Present in Visceral Adipose Tissue in Patients With Obesity-Related MASH

Research published in eBioMedicine showed that mitochondrial dysfunction is also present in visceral adipose tissue (VAT) in patients who have metabolic dysfunction-associated steatohepatitis (MASH). This may result in a disruption within the metabolic equilibrium of lipid processing and storage, therefore, impacting the liver and accelerating harmful adaptive responses in patients with MASH.¹

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The storage of fat in humans is closely associated with the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and the more severe form, MASH. Therefore, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH. For this case-control, observational study¹, the investigators enrolled 100 patients undergoing bariatric surgery who were enrolled from a prior clinical trial (NCT05554224)², which aimed to analyze samples provided by patients with obesity-associated MASLD and MASH at the multi-omics level.¹

In the prior study³, which was published in Clinical Nutrition, in which the main aim was to assess the effectiveness of surgically induced weight loss in patients with diabetes- or obesity-related fatty liver disease, the investigators observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared with their metabolically healthier overweight or obese counterparts.^2,3 Prior to surgery, oxylipins originating from lipoxygenase activity—such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE—were prevalent; however, 1 year following laparoscopic sleeve gastrectomy, there was a complex shift in the oxylipin profile, which favored species from the cyclooxygenase pathway, such as proinflammatory prostanoids (eg, TXB2, PGE2, PGD2, and 12-HHTrE). This change, according to the authors, appeared to be linked to a reduction in adiposity, emphasizing lipid turnover’s influence in the development of severe obesity-related metabolic disorders.³

Despite the reduction in fatty acid levels that are associated with weight loss, the oxylipin profile shifts towards a prevalence of more proinflammatory species. These data indicate that mechanistic approaches to address severe obesity are needed, emphasizing the importance of closely monitoring the metabolic adaptations after weight loss.³

For the current study¹, the investigators utilized a systems biology-based approach to analyze liver, abdominal subcutaneous adipose tissue (SAT), omental VAT, and blood. MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples, and lipidomics and proteomics profiles were determined on plasma samples.

The data demonstrated that liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Additionally, paired adipose tissue biopsies were observed to have larger adipocyte areas in both fat depots in MASH. Further enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics also identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840–0.979) for effectively screening MASH.¹

The findings suggest that circulating lipids serve as potential biomarkers for MASH, offering a non-invasive alternative for diagnosis in patients with severe obesity, the authors noted. By utilizing the systems biology approach, this study shows the multi-omics profiles of liver tissue and 2 distinct adipose tissue depots from patients with severe obesity, with and without MASH. Additionally, the minimization of confounding factors—including adipose tissue amount and distribution—can lead to significant differences in mitochondrial lipid metabolism in VAT.¹

REFERENCES

1. Castañé H, Jiménez-Franco A, Hernández-Aguilera A, et al. Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatophepatitis. eBioMedicine. 2025;111:105532. doi:10.1016/j.ebiom.2024.105532

2. Integrated Multi-omics Data for Personalized Treatment of Obesity-associated Fatty Liver Disease. ClinicalTrials.gov identifier: NCT05554224. Updated November 13, 2024. Accessed January 21, 2025. https://clinicaltrials.gov/study/NCT05554224

3. Jiménez-Franco A, Castañé H, Martínez-Navidad C, et al. Metabolic adaptations in severe obesity: Insights from circulating oxylipins before and after weight loss. Clin Nutr. 2024;43(1):246-258. doi:10.1016/j.clnu.2023.12.002