Lipid molecular timeline profiling reveals diurnal crosstalk between the liver and circulation

Richard R Sprenger,Martin Hermansson,Ditte Neess,Lena Sokol Becciolini,Signe Bek Sørensen,Rolf Fagerberg,Josef Ecker,Gerhard Liebisch,Ole N Jensen,Dennis E Vance,Nils J Færgeman,Robin W Klemm,Christer S Ejsing

doi:10.1016/j.celrep.2021.108710

Abstract

Diurnal regulation of whole-body lipid metabolism plays a vital role in metabolic health. Although changes in lipid levels across the diurnal cycle have been investigated, the system-wide molecular responses to both short-acting fasting-feeding transitions and longer-timescale circadian rhythms have not been explored in parallel. Here, we perform time-series multi-omics analyses of liver and plasma revealing that the majority of molecular oscillations are entrained by adaptations to fasting, food intake, and the postprandial state. By developing algorithms for lipid structure enrichment analysis and lipid molecular crosstalk between tissues, we find that the hepatic phosphatidylethanolamine (PE) methylation pathway is diurnally regulated, giving rise to two pools of oscillating phosphatidylcholine (PC) molecules in the circulation, which are coupled to secretion of either very low-density lipoprotein (VLDL) or high-density lipoprotein (HDL) particles. Our work demonstrates that lipid molecular timeline profiling across tissues is key to disentangling complex metabolic processes and provides a critical resource for the study of whole-body lipid metabolism.

Highlights

Regulation and coordination of lipid metabolism at the wholebody level and around the diurnal cycle is of paramount importance for metabolic health
non-esterified fatty acids (NEFAs) can be used for energy production and synthesis of TAGs, which become incorporated into very low-density lipoprotein (VLDL) particles and secreted for transport back to adipose tissue
The importance of the TAG-NEFA cycle is exemplified by the treatment of type 2 diabetes with thiazolidinediones, which attenuates this process by increasing the TAG storage capacity of adipocytes, thereby reducing the NEFA release and ameliorating hyperlipidemia and insulin resistance (Soccio et al, 2014)

Summary

Introduction

Regulation and coordination of lipid metabolism at the wholebody level and around the diurnal cycle is of paramount importance for metabolic health. A prominent metabolic hallmark of fasting is the cycling of non-esterified fatty acids (NEFAs) and triacylglycerols (TAGs) between adipose tissue and the liver (Reshef et al, 2003). This process results from increased lipolysis of TAGs in adipose tissue and release of NEFAs into the circulation. Dietary fats are incorporated into chylomicrons, which are transported from the intestine via the lymph and circulation to adipose tissue for storage as TAGs (Bickerton et al, 2007)

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Conclusion