Abstract
Autophagy is a catabolic mechanism to degrade cellular components to maintain cellular energy levels during starvation, a condition where PPARα may be activated. Here we report a reduced autophagic capacity in the liver following chronic activation of PPARα with fenofibrate (FB) in mice. Chronic administration of the PPARα agonist FB substantially reduced the levels of multiple autophagy proteins in the liver (Atg3, Agt4B, Atg5, Atg7 and beclin 1) which were associated with a decrease in the light chain LC3II/LC3I ratio and the accumulation of p62. This was concomitant with an increase in the expression of lipogenic proteins mSREBP1c, ACC, FAS and SCD1. These effects of FB were completely abolished in PPARα-/- mice but remained intact in mice with global deletion of FGF21, a key downstream mediator for PPARα-induced effects. Further studies showed that decreased the content of autophagy proteins by FB was associated with a significant reduction in the level of FoxO1, a transcriptional regulator of autophagic proteins, which occurred independently of both mTOR and Akt. These findings suggest that chronic stimulation of PPARα may suppress the autophagy capacity in the liver as a result of reduced content of a number of autophagy-associated proteins independent of FGF21.
Highlights
Autophagy is a process to degrade and recycle dysfunctional cellular components via the lysosome in order to maintain cellular homeostasis [1]
We investigated whether the reduced autophagic proteins after chronic administration of FB may be mediated by FoxO1, a critical transcription factor regulating autophagic proteins
The present study investigated the effect of chronic activation of peroxisome proliferator-activated receptor α (PPARα) on liver autophagy in mice and the results revealed several novel findings
Summary
Autophagy is a process to degrade and recycle dysfunctional cellular components via the lysosome in order to maintain cellular homeostasis [1] It is important in maintaining energy during periods of starvation. Forkhead box O (FoxO) family proteins play an important role by controlling the expression of a number of autophagy related genes [3, 5, 6]. Another transcription factor that is critical for adaptive metabolism to starvation is peroxisome proliferator-activated receptor α (PPARα).
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