Author(s): YAO, Y., ZHANG, Y., XIAO, H., ZU, J., XU, Y., TANG, Q., LU, J., Institution: NANJING SPORT INSTITUTE, Country: CHINA, Abstract-ID: 1212

INTRODUCTION:
Metabolic-associated fatty liver disease (MAFLD) is often accompanied by the abnormal activation of hepatic pyroptosis. Gasdermin D (GSDMD)-mediated mitochondrial and cell membrane pore formation is the core mechanism regulating hepatic pyroptosis, and play a critical role in the pathophysiology of this disease. This study aimed to investigate the effects of exercise intervention on mitochondrial damage-mediated hepatic pyroptosis in MAFLD rats.
METHODS:
Fifty-six SD rats were randomly divided into three groups (n=14 each): normal control (NC), HFFC model (HC), and HFFC + exercise (HE), with an 8-week intervention. At the end, body and liver weights were measured. Blood samples were collected to detect serum ALT, AST, CHOL, TG, IL-18, and IL-1β. Liver tissue was homogenized to extract mitochondria and cytoplasm. Mitochondrial function was detected, and cytoplasm was used for 8-OHG detection. Frozen liver sections were subjected to immunofluorescence staining for GSDMD colocalization with WGA and TOM20.
RESULTS:
1)Compared with the NC group, the HC group showed a significant increase in body weight (+18.38%), liver index (+114.77%), and serum levels of ALT (+171.93%), AST (+220.08%), CHOL (+109.09%), and TG (+76.6%). In contrast, the HE group exhibited a significant decrease in the above indices compared with the HC group, with body weight (-9.22%), liver index (-26.24%), ALT (-37.26%), AST (-46.8%), CHOL (-44.16%), and TG (-39.02%) all reduced significantly (P<0.05).
2)Serum levels of IL-18 (24.07±2.32 vs 53.64±3.66 pg/mL), IL-1β (34.87±2.96 vs 93.68±5.06 pg/mL), and cytoplasmic 8-OHG level (2.31±0.20 vs 4.55±0.43) were significantly higher in the HC group than in the NC group, while these indices were markedly decreased in the HE group (IL-18: 23.97±2.70 pg/mL; IL-1β: 51.96±10.97 pg/mL; 8-OHG: 2.62±0.48) compared with the HC group (P<0.05).
3)The mitochondrial mitochondrial respiratory control ratio (RCR) respiratory control ratio value was significantly lower in the HC group than in the NC group (5.53±1.73 vs 3.82±0.87), whereas the colocalized positive areas of GSDMD with WGA (+75%) and GSDMD with TOM20 (+65.92%) were significantly increased. Compared with the HC group, the HE group had a significantly elevated of mitochondrial RCR (12.25±3.44) and a notable reduction in the colocalized positive areas of GSDMD with WGA (-30.15%) and GSDMD with TOM20 (-35.34%) (P<0.05).
CONCLUSION:
1)HFFC diet induces significant hepatic lipid accumulation and dyslipidemia, impairs mitochondrial respiratory function, and promotes mitochondrial damege-mediated membrane pore formation, thereby triggering hepatocyte pyroptosis.
2)Exercise intervention effectively alleviates hepatic lipid deposition and dyslipidemia, enhances mitochondrial function, and suppresses mitochondrial and cellular GSDMD pore formation, consequently mitigating mitochondrial mediated pyroptosis and exerting a protective effect against MAFLD.