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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
Author(s) -
Jia Yaoyao,
Kim JinYoung,
Jun HeeJin,
Kim SunJoong,
Lee JiHae,
Hoang Minh Hien,
Hwang KwangYeon,
Um SooJong,
Chang Hyo Ihl,
Lee SungJoon
Publication year - 2012
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201100798
Subject(s) - transactivation , peroxisome proliferator activated receptor , lipid metabolism , biology , receptor , fenofibrate , peroxisome proliferator activated receptor delta , agonist , biochemistry , nuclear receptor , chemistry , microbiology and biotechnology , gene expression , pharmacology , gene , transcription factor
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 PPAR δ/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 PPAR s 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.