A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use

被引：197

作者：

Liu, Sihao ^{[1
]}

Brown, Jonathan D. ^{[2
]}

Stanya, Kristopher J. ^{[1
]}

Homan, Edwin ^{[3
]}

Leidl, Mathias ^{[3
]}

Inouye, Karen ^{[1
]}

Bhargava, Prerna ^{[1
]}

Gangl, Matthew R. ^{[1
]}

Dai, Lingling ^{[1
,4
,5
]}

Hatano, Ben ^{[1
]}

Hotamisligil, Goekhan S. ^{[1
]}

Saghatelian, Alan ^{[3
]}

Plutzky, Jorge ^{[2
]}

Lee, Chih-Hao ^{[1
]}

机构：

[1] Harvard Univ, Sch Publ Hlth, Div Biol Sci, Dept Genet & Complex Dis, Boston, MA 02115 USA

[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc,Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Dept Chem, Cambridge, MA 02138 USA

[4] Cent South Univ, XiangYa Hosp, Good Clin Practice Off, Changsha 410000, Hunan, Peoples R China

[5] Cent South Univ, Inst Clin Pharmacol, Changsha 410000, Hunan, Peoples R China

来源：

NATURE | 2013年 / 502卷 / 7472期

基金：

美国国家卫生研究院;

关键词：

CIRCADIAN BEHAVIOR; ADIPOSE-TISSUE; METABOLISM; IDENTIFICATION; MASS; ALPHA; GLUCOSE; MICE;

D O I：

10.1038/nature12710

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding(1,2) and is repressed by Rev-erb alpha/beta and an HDAC3-containing complex(3-5) during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes(6-8), suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPAR delta-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPAR delta controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPAR delta activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPAR delta activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPAR alpha. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPAR delta-PC(18:0/18:1) signalling in metabolic disorders, including obesity.

引用

页码：550 / +

页数：17

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