Oxidative stress in metabolic dysfunction‐associated steatotic liver disease (MASLD): How does the animal model resemble human disease?

Despite decades of research, the pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) is still not completely understood. Based on the evidence from preclinical models, one of the factors proposed as a main driver of disease development is oxidative stress. This study aim...

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Published in:The FASEB journal 2024-02, Vol.38 (3), p.e23466-n/a
Main Authors: Jakubek, Patrycja, Kalinowski, Piotr, Karkucinska‐Wieckowska, Agnieszka, Kaikini, Aakruti, Simões, Inês C. M., Potes, Yaiza, Kruk, Beata, Grajkowska, Wieslawa, Pinton, Paolo, Milkiewicz, Piotr, Grąt, Michał, Pronicki, Maciej, Lebiedzinska‐Arciszewska, Magdalena, Krawczyk, Marcin, Wieckowski, Mariusz R.
Format: Article
Language:English
Subjects:
Animals
antioxidant defense system
Antioxidants
Chromatography, Liquid
Fatty Liver
Humans
Metabolic Diseases
Mice
Mice, Inbred C57BL
mitochondrial respiratory chain
Models, Animal
obese patients
oxidative damage
Oxidative Stress
reactive oxygen species
Tandem Mass Spectrometry
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Summary:Despite decades of research, the pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) is still not completely understood. Based on the evidence from preclinical models, one of the factors proposed as a main driver of disease development is oxidative stress. This study aimed to search for the resemblance between the profiles of oxidative stress and antioxidant defense in the animal model of MASLD and the group of MASLD patients. C57BL/6J mice were fed with the Western diet for up to 24 weeks and served as the animal model of MASLD. The antioxidant profile of mice hepatic tissue was determined by liquid chromatography‐MS3 spectrometry (LC–MS/MS). The human cohort consisted of 20 patients, who underwent bariatric surgery, and 6 controls. Based on histological analysis, 4 bariatric patients did not have liver steatosis and as such were also classified as controls. Total antioxidant activity was measured in sera and liver biopsy samples. The hepatic levels of antioxidant enzymes and oxidative damage were determined by Western Blot. The levels of antioxidant enzymes were significantly altered in the hepatic tissue of mice with MASLD. In contrast, there were no significant changes in the antioxidant profile of hepatic tissue of MASLD patients, except for the decreased level of carbonylated proteins. Decreased protein carbonylation together with significant correlations between the thioredoxin system and parameters describing metabolic health suggest alterations in the thiol‐redox signaling. Altogether, these data show that even though the phenotype of mice closely resembles human MASLD, the animal‐to‐human translation of cellular and molecular processes such as oxidative stress may be more challenging. This study aimed to compare redox profiles between the MASLD mice and MASLD patients. In contrast to the animal model, the manifestation of oxidative stress was not detected in patients. We identified common thiol‐redox signaling‐related parameters that were affected in both patients and MASLD mice. These findings challenge the one‐to‐one translation of redox‐related findings between MASLD mice and patients. The evidence of potential alterations in thiol‐redox signaling may constitute a novel target in the development of drugs for MASLD treatment.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202302447R