Exercise enhances hepatic mitochondrial structure and function while preventing endoplasmic reticulum stress and metabolic dysfunction-associated steatotic liver disease in mice fed a high-fat diet.

• High-intensity interval training (HIIT) avoided liver steatosis in high-fat-fed mice. • HIIT (thrice weekly) prevented hyperglycemia and endoplasmic reticulum (ER) stress. • HIIT preserved mitochondrial ultrastructure and enhanced beta-oxidation. • HIIT targeted ER and mitochondrial homeostasis to prevent liver steatosis. Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted increasing attention from the scientific community because of its severe but silent progression and the lack of specific treatment. Glucolipotoxicity triggers endoplasmic reticulum (ER) stress with decreased beta-oxidation and enhanced lipogenesis, promoting the onset of MASLD, whereas regular physical exercise can prevent MASLD by preserving ER and mitochondrial function. Thus, the hypothesis of this study was that high-intensity interval training (HIIT) could prevent the development of MASLD in high-fat (HF)-fed C57BL/6J mice by maintaining insulin sensitivity, preventing ER stress, and promoting beta-oxidation. Forty male C57BL/6J mice (3 months old) comprised 4 experimental groups: the control (C) diet group, the C diet + HIIT (C-HIIT) group, the HF diet group, and the HF diet + HIIT (HF-HIIT) group. HIIT sessions lasted 12 minutes and were performed 3 times weekly by trained mice. The diet and exercise protocols lasted for 10 weeks. The HIIT protocol prevented weight gain and maintained insulin sensitivity in the HF-HIIT group. A chronic HF diet increased ER stress-related gene and protein expression, but HIIT helped to maintain ER homeostasis, preserve mitochondrial ultrastructure, and maximize beta-oxidation. The increased sirtuin-1/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha expression implies that HIIT enhanced mitochondrial biogenesis and yielded adequate mitochondrial dynamics. High hepatic fibronectin type III domain containing 5 /irisin agreed with the antilipogenic and anti-inflammatory effects observed in the HF-HIIT group, reinforcing the antisteatotic effects of HIIT. Thus, we confirmed that practicing HIIT 3 times per week maintained insulin sensitivity, prevented ER stress, and enhanced hepatic beta-oxidation, impeding MASLD development in this mouse model even when consuming high energy intake from saturated fatty acids. HIIT prevented overweight and liver steatosis by mitochondrial and ER enhancement. Abbreviations: ACOX1, acyl-coenzyme A oxidase 1; Atf4 , activating transcription factor 4; ER, endoplasmic reticulum; GRP78, glucose-regulated protein 78; Chop , C/EBP homologous protein; Fgf21 , fibroblast growth factor 21; Gadd45 , growth arrest and DNA damage-inducible 45; Ppar , peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (Pgc1-a); Xbp-a , X-box binding protein 1. Created with www.biorender.com. [Display omitted] [ABSTRACT FROM AUTHOR]