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

Oct 25, 2013Nature

Daily changes in blood fats reflect liver fat production and body fat use

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Abstract

PPARδ-dependent de novo lipogenesis in the liver regulates muscle fat use via the lipid phosphatidylcholine 18:0/18:1.

Hepatic lipogenesis follows a circadian rhythm, with peak activity during nighttime feeding.
Rev-erbα/β and an HDAC3 complex repress lipogenesis during the day.
Liver-specific activation of PPARδ increases muscle fatty acid uptake, while deletion of hepatocyte PPARδ decreases it.
The serum lipid phosphatidylcholine 18:0/18:1 is regulated by diurnal hepatic PPARδ activity and influences postprandial lipid levels.
High-fat feeding reduces the rhythmic production of phosphatidylcholine 18:0/18:1.
Administration of phosphatidylcholine 18:0/18:1 in db/db mice improves metabolic homeostasis.

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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 and is repressed by Rev-erbα/β and an HDAC3-containing complex 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, 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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A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use

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