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. 2024 Aug;80(3):697-712.
doi: 10.1007/s13105-024-01044-9. Epub 2024 Sep 12.

SIRT1 and FOXO1 role on MASLD risk: effects of DHA-rich n-3 PUFA supplementation and exercise in aged obese female mice and in post-menopausal overweight/obese women

Jinchunzi Yang  1   2 , Elisa Félix-Soriano  1 , Alejandro Martínez-Gayo  1 , Javier Ibañez-Santos  3 , Neira Sáinz  1 , J Alfredo Martínez  1   4 , María J Moreno-Aliaga  5   6   7
Affiliations

SIRT1 and FOXO1 role on MASLD risk: effects of DHA-rich n-3 PUFA supplementation and exercise in aged obese female mice and in post-menopausal overweight/obese women

Jinchunzi Yang et al. J Physiol Biochem. 2024 Aug.

Abstract

Sirtuins 1 (SIRT1) and Forkhead box protein O1 (FOXO1) expression have been associated with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Exercise and/or docosahexaenoic acid (DHA) supplementation have shown beneficial effects on MASLD. The current study aims to assess the relationships between Sirt1, Foxo1 mRNA levels and several MASLD biomarkers, as well as the effects of DHA-rich n-3 PUFA supplementation and/or exercise in the steatotic liver of aged obese female mice, and in peripheral blood mononuclear cells (PBMCs) of postmenopausal women with overweight/obesity. In the liver of 18-month-old mice, Sirt1 levels positively correlated with the expression of genes related to fatty acid oxidation, and negatively correlated with lipogenic and proinflammatory genes. Exercise (long-term treadmill training), especially when combined with DHA, upregulated hepatic Sirt1 mRNA levels. Liver Foxo1 mRNA levels positively associated with hepatic triglycerides (TG) content and the expression of lipogenic and pro-inflammatory genes, while negatively correlated with the lipolytic gene Hsl. In PBMCs of postmenopausal women with overweight/obesity, FOXO1 mRNA expression negatively correlated with the hepatic steatosis index (HSI) and the Zhejiang University index (ZJU). After 16-weeks of DHA-rich PUFA supplementation and/or progressive resistance training (RT), most groups exhibited reduced MASLD biomarkers and risk indexes accompanying with body fat mass reduction, but no significant changes were found between the intervention groups. However, in PBMCs n-3 supplementation upregulated FOXO1 expression, and the RT groups exhibited higher SIRT1 expression. In summary, SIRT1 and FOXO1 could be involved in the beneficial mechanisms of exercise and n-3 PUFA supplementation related to MASLD manifestation.

Keywords: Aging; DHA; Exercise training; FOXO1; MASLD; Overweight/obesity, post-menopause; SIRT1.

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Conflict of interest statement

The authors declare no competing interest concerning this research.

Figures

Fig. 1
Fig. 1
Effects of a long-term DHA-enriched HFD and/or exercise intervention on the mRNA expression level of Sirt1 (A), and correlations between the expression levels of Sirt1 and lipid metabolism-related genes (B-E) and pro-inflammatory genes (F-G) in the liver of aged obese female mice. Data are expressed as mean ± SD. n = 6–10. *** p < 0.001 vs. C group; ### p < 0.001 vs. DIO group; ††† p < 0.001 for DIO + DHA vs. DIO + DHA + EX group; c p < 0.001 for DIO + EX vs. DIO + DHA + EX group. Correlation analyses were carried out using Pearson or Spearman correlation coefficients after testing for normality
Fig. 2
Fig. 2
Effects of a long-term DHA-enriched HFD and/or treadmill exercise intervention on the mRNA expression level of Foxo1 (A), and correlations between the expression levels of Foxo1 and liver triglyceride (TG) content (B) and lipid metabolism-related genes (C-F) and pro-inflammatory genes (G) in the liver of aged obese female mice. Data are expressed as mean ± SD. n = 6–10. *** p < 0.001 vs. C group; † p < 0.05 for DIO + DHA vs. DIO + DHA + EX group. Correlation analyses were carried out using Pearson or Spearman correlation coefficients after testing for normality
Fig. 3
Fig. 3
Effects of 16-week intervention with a DHA-rich n-3 PUFA supplementation and/or RT program on SIRT1 mRNA expression in PBMCs (A-B) and correlation between changes of SIRT expression and baseline MASLD indexes (C) in postmenopausal women with overweight/obesity. Baseline-endpoint differences were studied by paired Student’s t-test or Wilcoxon’s signed-rank test after testing for normality. Differences in changes between groups were compared by two-way ANOVA. Data are expressed as mean ± SD. n = 14–16 per group. *p < 0.05. ns nonsignificant
Fig. 4
Fig. 4
Effects of 16-week intervention with a DHA-rich n-3 PUFA supplementation and/or RT program on FOXO1 mRNA expression in PBMCs (A-B) and correlation between changes of FOXO1 expression and baseline MASLD indexes (C) in postmenopausal women with overweight/obesity. Baseline-endpoint differences were studied by paired Student’s t-test or Wilcoxon’s signed-rank test after testing for normality. Differences in changes between groups were compared by two-way ANOVA. Data are expressed as mean ± SD. n = 14–16 per group. ** p < 0.01, *** p < 0.001. ns nonsignificant
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