Abstract
Background
A high-calorie diet and lack of exercise are the primary risk factors contributing to metabolic associated fatty liver disease (MAFLD) initiation and progression. Although mitochondrial dysfunction in MAFLD has been widely recognized, the precise molecular mechanisms of mitochondrial function alteration during MAFLD development remain to be fully elucidated.
Methods
A total of sixty male C57/black mice were maintained on a normal or amylin liver NASH (AMLN) diet for 6 and 10 weeks. Half of the AMLN diet mice were then subjected to 8 weeks of voluntary wheel running with an AMLN diet persistently, while the other AMLN diet mice were sedentary until 14 and 18 weeks. After the experimental intervention, the mice were sacrificed under anesthesia, blood and liver tissue were collected for further analysis. Changes in biochemical parameters, histopathology, lipid accumulation, endoplasmic reticulum stress, mitochondrial function and mitochondrial unfolded protein response-related proteins were assessed and correlation analysis of serum FGF21 and mitochondrial unfolded genes expression was also performed.
Results
The results showed that the hepatic lipid deposition and PERK-eIF2α-ATF4 pathway activation were significant increased with prolonged duration of AMLN diet. However, expression of mitochondrial unfolded protein response (UPRmt) genes, such as LONP1, HSP60, and HSP70, as well as mitokine FGF21 secretion were significantly enhanced in the 14-week AMLN diet mice, but were markedly reduced with the excessive lipid deposition induced by the 18-week AMLN diet. In addition, there is a significant positive correlation between circulating FGF21 and the amount of mitochondrial unfolded genes expression during MAFLD progression. Moreover, exercise intervention significantly rescued the hepatic phenotype through improving mitochondrial function, regulating UPRmt activation pattern and increasing FGF21 secretion.
Conclusions
During the development of AMLN diet-induced MAFLD, the relationship between the degree of lipid deposition and mitochondrial function is not a linear model of negatively correlation. Instead, mitochondria could experience self-remodeling at the earlier stage of lipid accumulation, then lose their self-repair ability due to lipid overload. Exercise effectively prevents excessive lipid deposition, through regulating UPRmt, remodeling mitochondrial protein homeostasis and promoting the secretion of mitokine FGF21, which plays an essential role in delaying the MAFLD occurrence and progression.