Chronic activation of PPARα with fenofibrate reduces autophagic proteins in the liver of mice independent of FGF21

• Published in: PloS one 2017-04, Vol.12 (4), p.e0173676
• Main Authors: Jo, Eunjung, Li, Songpei, Liang, Qingning, Zhang, Xinmei, Wang, Hao, Herbert, Terence P, Jenkins, Trisha A, Xu, Aimin, Ye, Ji-Ming
• Format: Article
• Language: English
• Subjects: Acclimatization; Acetaminophen; Acetylation; Activation; Activation analysis; Adipose tissue; Age; AKT protein; AKT1 protein; AMP; AMP-activated protein kinase; Animal welfare; Animals; Assaying; Autophagy; Autophagy - drug effects; Autophagy - genetics; Autophagy-Related Protein 5 - antagonists & inhibitors; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Autophagy-Related Protein 7 - antagonists & inhibitors; Autophagy-Related Protein 7 - genetics; Autophagy-Related Protein 7 - metabolism; Autophagy-Related Proteins - antagonists & inhibitors; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Beclin-1 - genetics; Beclin-1 - metabolism; Biochemistry; Biology; Biology and Life Sciences; Biotechnology; Blood Glucose - metabolism; Body weight; Calories; Cardiomyocytes; Cell death; Centrifugation; Chloroform; Circulation; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Diabetes; Diabetes mellitus; Drug abuse; Drugs; Epinephrine; Ethanol; fas Receptor - genetics; fas Receptor - metabolism; Fasting; Fatty acids; Fenofibrate - pharmacology; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblasts; Food intake; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Gene Expression Regulation - drug effects; Glass; Glucose; Growth factors; Heart diseases; Hepatotoxicity; Homeostasis; Inhibition; Insulin; Insulin resistance; Kinases; Laboratories; Liver; Liver - drug effects; Liver - metabolism; Medicine; Medicine and Health Sciences; Metabolism; Methanol; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Nitrogen; Nuclear fuels; Nutrient status; Nutrients; Oxidation; Pharmacology; Physical Sciences; Physiology; PPAR alpha - agonists; PPAR alpha - genetics; PPAR alpha - metabolism; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Research and Analysis Methods; Rodents; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Signal Transduction; Stearoyl-CoA Desaturase - genetics; Stearoyl-CoA Desaturase - metabolism; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Studies; Temperature effects; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Triglycerides; Triglycerides - metabolism; Ubiquitin-Conjugating Enzymes - antagonists & inhibitors; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Weight reduction
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0173676

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.