Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist

被引:44
|
作者
Goto, Tsuyoshi [1 ,6 ]
Nagai, Hiroyuki [1 ]
Egawa, Kahori [1 ]
Kim, Young-Il [1 ]
Kato, Sota [1 ]
Taimatsu, Aki [1 ]
Sakamoto, Tomoya [1 ]
Ebisu, Shogo [2 ]
Hohsaka, Takahiro [3 ]
Miyagawa, Hiroh [4 ]
Murakami, Shigeru [5 ]
Takahashi, Nobuyuki [1 ,6 ]
Kawada, Teruo [1 ,6 ]
机构
[1] Kyoto Univ, Grad Sch Agr, Div Food Sci & Biotechnol, Lab Mol Funct Food, Uji, Kyoto 6110011, Japan
[2] Prot Express Co Ltd, Chiba 2880041, Japan
[3] Japan Adv Inst Sci & Technol, Sch Mat Sci, Nomi, Ishikawa 9231292, Japan
[4] Taisho Pharmaceut Co Ltd, Kita Ku, Saitama 3119530, Japan
[5] Taisho Pharmaceut Co Ltd, Toshima Ku, Tokyo 1708633, Japan
[6] Kyoto Univ, Res Unit Physiol Chem, Kyoto 6068501, Japan
关键词
adipocyte differentiation; farnesyl pyrophosphate (FPP); ligand; metabolic syndrome; mevalonate metabolite; peroxisome-proliferator-activated receptor gamma (PPAR gamma); ACTIVATED-RECEPTOR-GAMMA; 3T3-L1; ADIPOCYTES; GENE-EXPRESSION; INSULIN-RESISTANCE; TRANSCRIPTIONAL COACTIVATORS; EFFICIENT GENERATION; METABOLIC SYNDROME; HEPG2; HEPATOCYTES; LIPID-METABOLISM; CONTROLLED-TRIAL;
D O I
10.1042/BJ20101939
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPAR gamma (peroxisome-proliferator-activated receptor gamma), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPAR gamma systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPAR gamma in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)-PPAR gamma. Direct binding of FPP to PPAR gamma was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPAR gamma target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPAR gamma-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPAR gamma-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPAR gamma agonist and regulate gene expression in adipocytes.
引用
收藏
页码:111 / 119
页数:9
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