Exercise attenuates high-fat diet-induced liver injury in mice via PPARα pathway and reduction of oxidative stress and inflammation.

Fat acts as a “double-edged sword”—while serving as essential energy for the body, excessive long-term intake can lead to metabolic disorders and liver damage. With social progress and lifestyle changes, liver injury caused by chronic high-fat diet (HFD) has become a widespread and serious public health concern. In consideration of the unique role of exercise in lipid metabolism, we subjected mice to an HFD to investigate its effects on the livers of mice using RNA-Seq and other methods and comprehensively explore the mechanism of exercise’s regulatory effects on liver damage in HFD mice. Our results demonstrated that HFD could induce PPARα downregulation in the livers of mice, disrupt redox homeostasis, and trigger NF-κB-mediated inflammatory cascades, resulting in severe liver damage. Exercise can activate PPARα, inhibit NF-κB, reduce macrophage aggregation, as well as enhance HO-1 and SOD1 expression to regulate redox balance and inflammation. It is worth noting that HFD induces an increase in pro-oxidant activity and a decrease in antioxidant activity in the livers of mice, placing them in a state of oxidative stress. However, exercise simultaneously increases both pro-oxidant and antioxidant levels, alleviating oxidative stress. These results indicate that exercise can activate PPARα and regulate redox balance and inflammation, thereby protecting the livers of mice from the effects of HFD.