Dataset Information

Chronic activation of PPAR? with fenofibrate reduces autophagic proteins in the liver of mice independent of FGF21.

ABSTRACT: Autophagy is a catabolic mechanism to degrade cellular components to maintain cellular energy levels during starvation, a condition where PPAR? may be activated. Here we report a reduced autophagic capacity in the liver following chronic activation of PPAR? with fenofibrate (FB) in mice. Chronic administration of the PPAR? 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 PPAR?-/- mice but remained intact in mice with global deletion of FGF21, a key downstream mediator for PPAR?-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 PPAR? may suppress the autophagy capacity in the liver as a result of reduced content of a number of autophagy-associated proteins independent of FGF21.

SUBMITTER: Jo E

PROVIDER: S-EPMC5396863 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Jo Eunjung E Li Songpei S Liang Qingning Q Zhang Xinmei X Wang Hao H Herbert Terence P TP Jenkins Trisha A TA Xu Aimin A Ye Ji-Ming JM

PloS one 20170419 4

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 lig ...[more]

PMID: 28422956

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Project description:Background & aimsThe prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.MethodsThe clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.ResultsSerum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.ConclusionsLiver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.

Dataset Information

Chronic activation of PPAR? with fenofibrate reduces autophagic proteins in the liver of mice independent of FGF21.

Publications

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

Similar Datasets

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