西亞試劑：A diurnal serum lipid integrates hepatic lipogenesis and pe

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

Sihao Liu，Jonathan D. Brown，Kristopher J. Stanya，Edwin Homan，Leidl，Karen Inouye，Prerna Bhargava，Matthew R. Gangl，Lingling Dai，Ben Hatano，Gokhan S. Hotamisligil，Alan Saghatelian，Jorge Plutzky& Chih-Hao Lee

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 feeding1， 2 and is repressed by Rev-erbα/β and an HDAC3-containing complex3， 4， 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 phenotypes6， 7， 8， suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ 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 PPARδ activity. PC(18：0/18：1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. 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 PPARδ–PC(18：0/18：1) signalling in metabolic disorders， including obesity.

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