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.
MeSH terms
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Animals
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Autophagy / drug effects*
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Autophagy / genetics
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Autophagy-Related Protein 5 / antagonists & inhibitors
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Autophagy-Related Protein 5 / genetics
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Autophagy-Related Protein 5 / metabolism
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Autophagy-Related Protein 7 / antagonists & inhibitors
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Autophagy-Related Protein 7 / genetics
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Autophagy-Related Protein 7 / metabolism
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Autophagy-Related Proteins / antagonists & inhibitors
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Autophagy-Related Proteins / genetics
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Autophagy-Related Proteins / metabolism
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Beclin-1 / genetics
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Beclin-1 / metabolism
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Blood Glucose / metabolism
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism
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Fenofibrate / pharmacology*
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism
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Forkhead Box Protein O1 / genetics
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Forkhead Box Protein O1 / metabolism
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Gene Expression Regulation / drug effects*
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Liver / drug effects*
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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PPAR alpha / agonists*
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PPAR alpha / genetics
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PPAR alpha / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Sequestosome-1 Protein / genetics
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Sequestosome-1 Protein / metabolism
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Signal Transduction
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Stearoyl-CoA Desaturase / genetics
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Stearoyl-CoA Desaturase / metabolism
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Triglycerides / metabolism
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Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
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Ubiquitin-Conjugating Enzymes / genetics
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Ubiquitin-Conjugating Enzymes / metabolism
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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Atg5 protein, mouse
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Atg7 protein, mouse
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Autophagy-Related Protein 5
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Autophagy-Related Proteins
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Beclin-1
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Becn1 protein, mouse
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Blood Glucose
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Fas protein, mouse
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Forkhead Box Protein O1
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Foxo1 protein, mouse
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Map1lc3b protein, mouse
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Microtubule-Associated Proteins
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PPAR alpha
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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Srebf1 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Triglycerides
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fas Receptor
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fibroblast growth factor 21
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Fibroblast Growth Factors
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Scd1 protein, mouse
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Stearoyl-CoA Desaturase
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Ubiquitin-Conjugating Enzymes
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mTOR protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Atg4b protein, mouse
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Cysteine Endopeptidases
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Autophagy-Related Protein 7
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Atg3 protein, mouse
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Fenofibrate
Grants and funding
This work was funded by a National Health and Medical Research Council of Australia Program Grant 535921 (allocation to JM Ye), Diabetes Australia Research Program GG12314 (allocation to JM Ye), and Block Grant Earmarked for Research (104) (201109176145) (allocation to A Xu).