Systematic assessment of lipid profiles for the discovery of tissue contributors to the circulating lipid pool in cold exposure

Abstract

Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease as well as acute stresses such as fasting and cold exposure. Advances in mass spectrometry based lipidomics have uncovered the complexity of the plasma lipidome which includes over 500 lipids that serve functional roles including energy substrate and signaling molecule. The plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge is establishing the tissues of origin and uptake for various plasma lipids, which is necessary to determine the lipid function. Using cold exposure as an acute stress, we performed global lipidomics on the plasma and nine tissues that may contribute to the circulating pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides were significantly changed with cold exposure. Through computational assessment, we identified the liver and brown adipose tissue (BAT) as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the BAT and kidney as regulators of the plasma ceramide pool. These studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have implications in understanding the function of plasma ACars and ceramides, which are elevated in metabolic diseases. SummaryThere are over 500 identified lipids in circulating plasma, many without known origin or function. Using untargeted lipidomics on plasma and nine other tissues of cold exposed mice, we identified novel regulation of circulating acylcarnitines through the kidney and intestine, and a multiorgan system that regulates plasma ceramides. Our findings offer new targets for the study and functional characterization of circulating lipids in acute cold exposure and a computational resource for other investigators to explore multi-tissue lipidome remodeling during cold exposure. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY HighlightsO_LIGlobal lipidomics atlas of 9 tissues and plasma demonstrate dynamic shift with cold exposure. C_LIO_LIAdaptive resource for the selection of extraction method, data processing, and data analysis of multi-tissue global lipidomics data. C_LIO_LIRegression analysis identified the liver, BAT, intestine, and kidney as regulators of the plasma acylcarnitine pool that are not apparent by lipid levels alone. C_LIO_LIAcute cold exposure increases plasma ceramide levels, with the BAT and kidney as major contributors C_LI