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PPARα Is Regulated by miR-21 and miR-27b in Human Liver

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ABSTRACT

Purpose

Peroxisome proliferator-activated receptor α (PPARα) is an important transcriptional factor that regulates genes encoding endo/xenobiotic enzymes and lipid metabolizing enzymes. In this study, we investigated whether microRNAs (miRNAs) are involved in the regulation of PPARα in human liver.

Methods

Precursor or antisense oligonucleotide for miR-21 or miR-27b was transfected into HuH7 cells; expression of PPARα and acyl-CoA synthetase M2B was determined by Western blot and real-time RT-PCR. Luciferase assay was performed to identify the functional miRNA recognition element (MRE). Expression levels of PPARα, miR-21, and miR-27b in a panel of 24 human livers were determined.

Results

The overexpression and inhibition of miR-21 or miR-27b in HuH7 cells significantly decreased and increased the PPARα protein level, respectively, but not PPARα mRNA level. The miRNA-dependent regulation of PPARα affected the expression of its downstream gene. Luciferase assay identified a functional MRE for miR-21 in the 3′-untranslated region of PPARα. In human livers, the PPARα protein levels were not correlated with PPARα mRNA, but inversely correlated with the miR-21 levels, suggesting a substantial impact of miR-21, although the contribution of miR-27b could not be ruled out.

Conclusions

We found that PPARα in human liver is regulated by miRNAs.

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Abbreviations

ACS:

acyl-CoA synthetase

AsO:

antisense LNA/DNA oligonucleotide

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

fetal bovine serum

IL-6:

interleukin-6

LNA:

locked nucleic acid

miRNA:

microRNA

MRE:

miRNA recognition element

PPAR:

peroxisome proliferator-activated receptor

RXR:

retinoid X receptor

Stat3:

signal transducer and activator of transcription 3

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ACKNOWLEDGMENTS

This work was supported in part by Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science. We acknowledge Mr. Brent Bell for reviewing the manuscript.

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Authors and Affiliations

  1. Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920–1192, Japan

    Katsuhiko Kida, Miki Nakajima, Takuya Mohri, Yuki Oda, Shingo Takagi, Tatsuki Fukami & Tsuyoshi Yokoi

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  1. Katsuhiko Kida
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  2. Miki Nakajima
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  3. Takuya Mohri
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  4. Yuki Oda
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  5. Shingo Takagi
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  7. Tsuyoshi Yokoi
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Correspondence to Tsuyoshi Yokoi.

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Kida, K., Nakajima, M., Mohri, T. et al. PPARα Is Regulated by miR-21 and miR-27b in Human Liver. Pharm Res 28, 2467–2476 (2011). https://doi.org/10.1007/s11095-011-0473-y

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  • DOI: https://doi.org/10.1007/s11095-011-0473-y

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