Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver

被引：495

作者：

Chakravarthy, Manu V. ^{[1
]}

Lodhi, Irfan J. ^{[1
]}

Yin, Li ^{[1
]}

Malapaka, Raghu R. V. ^{[3
]}

Xu, H. Eric ^{[3
]}

Turk, John ^{[1
]}

Semenkovich, Clay F. ^{[1
,2
]}

机构：

[1] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA

[3] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA

来源：

CELL | 2009年 / 138卷 / 03期

关键词：

PROLIFERATOR-ACTIVATED RECEPTORS; TANDEM MASS-SPECTROMETRY; ELECTROSPRAY-IONIZATION; FATTY-ACID; BINDING DOMAIN; PHOSPHOLIPIDS; PHOSPHATIDYLCHOLINE; EICOSANOIDS; GAMMA; MICE;

D O I：

10.1016/j.cell.2009.05.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The nuclear receptor PPAR alpha is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPAR alpha-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPAR alpha ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPAR alpha isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPAR alpha agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPAR alpha-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPAR alpha ligand-binding domain and coactivator peptide motifs was comparable to PPAR alpha agonists, but interactions with PPAR delta were weak and none were detected with PPAR gamma. Portal vein infusion of 16:0/18:1-GPC induced PPAR alpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPAR alpha ligand.

引用

页码：476 / 488

页数：13

共 45 条

[1]

Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARγ by FABP4 [J].

Ayers, Stephen D. ;

Nedrow, Katherine L. ;

Gillilan, Richard E. ;

Noy, Noa .

BIOCHEMISTRY, 2007, 46 (23) :6744-6752

[2]

Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome? [J].

Barter, Philip J. ;

Rye, Kerry-Anne .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2008, 28 (01) :39-46

[3]

Integration of metabolism and inflammation by lipid-activated nuclear receptors [J].

Bensinger, Steven J. ;

Tontonoz, Peter .

NATURE, 2008, 454 (7203) :470-477

[4]

Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor-null mice [J].

Bernal-Mizrachi, C ;

Weng, S ;

Feng, C ;

Finck, BN ;

Knutsen, RH ;

Leone, TC ;

Coleman, TY ;

Mecham, RP ;

Kelly, DP ;

Semenkovich, CF .

NATURE MEDICINE, 2003, 9 (08) :1069-1075

[5]

Crystal structure of the ligand-binding domain of the ultraspiracle protein USP, the ortholog of retinoid X receptors in insects [J].

Billas, IML ;

Moulinier, L ;

Rochel, N ;

Moras, D .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (10) :7465-7474

[6]

Brain fatty acid synthase activates PPARα to maintain energy homeostasis [J].

Chakravarthy, Manu V. ;

Zhu, Yimin ;

Lopez, Miguel ;

Yin, Li ;

Wozniak, David F. ;

Coleman, Trey ;

Hu, Zhiyuan ;

Wolfgang, Michael ;

Vidal-Puig, Antonio ;

Lane, M. Daniel ;

Semenkovich, Clay F. .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (09) :2539-2552

[7]

New hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis [J].

Chakravarthy, MV ;

Pan, ZJ ;

Zhu, YM ;

Tordjman, K ;

Schneider, JG ;

Coleman, T ;

Turk, J ;

Semenkovich, CF .

CELL METABOLISM, 2005, 1 (05) :309-322

[8]

The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation [J].

Clayton, GM ;

Peak-Chew, SY ;

Evans, RM ;

Schwabe, JWR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (04) :1549-1554

[9]

Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-α) in the development of inflammatory bowel disease in mice [J].

Cuzzocrea, S ;

Di Paola, R ;

Mazzon, E ;

Genovese, T ;

Muià, C ;

Centorrino, T ;

Caputi, AP .

LABORATORY INVESTIGATION, 2004, 84 (12) :1643-1654

[10]

Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor γ ligands and agonists [J].

Davies, SS ;

Pontsler, AV ;

Marathe, GK ;

Harrison, KA ;

Murphy, RC ;

Hinshaw, JC ;

Prestwich, GD ;

St Hilaire, A ;

Prescott, SM ;

Zimmerman, GA ;

McIntyre, TM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (19) :16015-16023

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