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The natural carotenoid astaxanthin, a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes

Authors

  • Yaoyao Jia,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
    2. Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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  • Jin-Young Kim,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
    2. Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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  • Hee-Jin Jun,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
    2. Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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  • Sun-Joong Kim,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
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  • Ji-Hae Lee,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
    2. Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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  • Minh Hien Hoang,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
    2. Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
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  • Kwang-Yeon Hwang,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
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  • Soo-Jong Um,

    1. Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea
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  • Hyo Ihl Chang,

    1. Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
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  • Sung-Joon Lee

    Corresponding author
    1. Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
    • Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea
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Correspondence: Dr. Sung-Joon Lee, Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, 136-713 Republic of Korea

E-mail:junelee@korea.ac.kr

Fax: +82-2-925-1970

Abstract

Scope

A natural carotenoid abundant in seafood, astaxanthin (AX), has hypolipidemic activity, but its underlying mechanisms of action and protein targets are unknown. We investigated the molecular mechanism of action of AX in hepatic hyperlipidemia by measuring peroxisome proliferator-activated receptors (PPAR) activity.

Methods and results

We examined the binding of AX to PPAR subtypes and its effects on hepatic lipid metabolism. AX binding activated PPAR-α, but inhibited PPAR-γ transactivation activity in reporter gene assay and time-resolved fluorescence energy transfer analyses. AX had no effect on PPARδ/β transactivation. AX bound directly to PPAR-α and PPAR-γ with moderate affinity, as assessed by surface plasmon resonance experiments. The differential effects of AX on PPARs were confirmed by measuring the expression of unique responsive genes for each PPAR subtype. AX significantly reduced cellular lipid accumulation in lipid-loaded hepatocytes. Transcriptome analysis revealed that the net effects of stimulation with AX (100 μM) on lipid metabolic pathways were similar to those elicited by fenofibrate and lovastatin (10 μM each), with AX rewiring the expression of genes involved in lipid metabolic pathways.

Conclusion

AX is a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes.

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