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Peroxisome proliferator-activated receptor alpha mediates C/EBP homologous protein to protect mice from acute liver failure

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Abstract

Objective

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to ameliorate liver injury in cases of acute liver failure (ALF). However, its intrinsic protective molecular mechanisms remain largely undetermined. C/EBP homologous protein (CHOP) is an important mediator of lipopolysaccharide (LPS)-induced inflammation. The aim of the present study was to test the hypothesis that PPARα activation alleviates liver inflammation to protect mice from acute liver failure (ALF) mediated by CHOP.

Methods

In a murine model induced by d-galactosamine (d-GalN, 700 mg/kg) and LPS (10 μg/kg), Wy-14643 (6 mg/kg) was administered to activate PPARα. The mice of different groups were killed 6 h after d-GalN/LPS injection, and the liver and blood were collected for analysis. To find out whether PPARα activation protects the liver from injury due to inflammation by regulating CHOP, we used expression plasmid to increase CHOP expression and demonstrated how PPARα mediated CHOP to regulate inflammation in vivo and in vitro.

Results

The expression of PPARα was downregulated and the expression of CHOP was upregulated with the development of d-GalN/LPS-induced liver injury. The protective molecular mechanisms of PPARα activation were dependent on the expression of CHOP. Indeed, (1) PPARα activation decreased the expression of CHOP; on the other hand, PPARα knockdown increased the expression of CHOP in vivo; (2) the depressed liver inflammation by PPARα activation was due to the downregulation of CHOP expression, because overexpression of CHOP by transfect plasmid reversed liver protection and increased liver inflammation again; (3) in vitro, PPARα inhibition by siRNA treatment increased the expression of proinflammatory cytokines, and CHOP siRNA co-transfection reversed the expression of proinflammatory cytokines.

Conclusions

Here, we demonstrated that PPARα activation contributes to liver protection and decreases liver inflammation in ALF, particularly through regulating CHOP. Our findings may provide a rationale for targeting PPARα as a potential therapeutic strategy to ameliorate ALF.

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Abbreviations

ALF:

Acute liver failure

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ATF6α:

Activating transcription factor 6α

BMDMs:

Murine bone marrow-derived macrophages

CHOP:

C/EBP homologous protein

CXCL-10:

Chemokine (C-X-C motif) ligand-10

d-GalN:

d-Galactosamine

ER:

Endoplasmic reticulum

H&E:

Hematoxylin and eosin

HPRT:

Hypoxanthine-guanine phosphoribosyltransferase

IL-6:

Interleutin-6

IRE1α:

Inositol-requiring kinase 1α

LPS:

Lipopolysaccharide

NF-κB:

Transcription factor nuclear factor-κB

NOD:

Nucleotide-binding oligomerization domain

PPARα:

Peroxisome proliferator-activated receptor-α

PERK:

Pancreatic ER eIF2α kinase

PVDF:

Polyvinylidene difluoride

qRT-PCR:

Quantitative reverse transcription-PCR

RIDD:

Regulated IRE1-dependent decay

RIG-1:

Retinoic acid-inducible gene 1

RIPA:

Radioimmunoprecipitation assay

STAT1:

Signal transducer and activator of transcription 1

TNF-α:

Tumor necrosis factor-α

UPR:

Unfolded protein responses

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (nos. 81270532, 81372094 and 81473500), the Natural Science Foundation of Beijing Municipality (no. 7162085), Beijing Municipal Science & Technology Commission Applied Research for the Clinical Characteristics of Capital (no. Z161100000516113), the Wang Boen Liver Fibrosis Research Foundation of CFHPC (no. CFHPC20131031), and the High-level Technical Personnel Training Plan of the Beijing Health System (no. 2013-3-075).

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Author notes

  1. Xiangying Zhang and Peiling Dong have contributed equally to this study.

Authors and Affiliations

  1. Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China

    Xiangying Zhang, Peiling Dong, Hongbo Shi, Huaying Sun, Dexi Chen, Zhongping Duan, Xiuhui Li & Feng Ren

  2. Menchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China

    Jianhui Lin

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  1. Xiangying Zhang
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Contributions

XL and FR conceived and designed the work. XZ and PD performed the experiments. HS and HS contributed reagents/materials/analysis tools. DC and ZD participated in the discussion of the study.

Corresponding author

Correspondence to Feng Ren.

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The authors declare no conflicts of interest.

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Responsible Editor: Liwu Li.

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Zhang, X., Dong, P., Shi, H. et al. Peroxisome proliferator-activated receptor alpha mediates C/EBP homologous protein to protect mice from acute liver failure. Inflamm. Res. 66, 813–822 (2017). https://doi.org/10.1007/s00011-017-1061-3

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  • DOI: https://doi.org/10.1007/s00011-017-1061-3

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