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


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.


CONCLUSIONS
AX is a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes.
Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul, Republic of Korea.
Yaoyao
Y
Jia
Jin-Young
JY
Kim
Hee-Jin
HJ
Jun
Sun-Joong
SJ
Kim
Ji-Hae
JH
Lee
Minh Hien
MH
Hoang
Kwang-Yeon
KY
Hwang
Soo-Jong
SJ
Um
Hyo Ihl
HI
Chang
Sung-Joon
SJ
Lee
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D031541:Fluorescence Resonance Energy Transfer; D020869:Gene Expression Profiling; D017930:Genes, Reporter / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008082:Lipotropic Agents / Q000378:metabolism / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance; D015533:Transcriptional Activation / Q000187:drug effects*; D024341:Xanthophylls / Q000378:metabolism / Q000494:pharmacology
D000975:Antioxidants; D008082:Lipotropic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D024341:Xanthophylls; C005948:astaxanthine