Summary of Study ST001289

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000871. The data can be accessed directly via it's Project DOI: 10.21228/M83M5X This work is supported by NIH grant, U2C- DK119886.

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Study IDST001289
Study TitleRegulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses
Study SummaryTo investigate the relationship between hypercholesterolemia, foam cell formation and inflammation, we performed lipidomic and transcriptomic analyses of elicited peritoneal macrophages in wild type (WT) or LDL receptor knockout (LDLR KO) mice fed either a normal cholesterol, normal fat (NCNF) diet or a high cholesterol, high fat (HCHF) 'Western' style diet. The combination of the LDLR KO genotype and the HCHF diet results in the formation of macrophage foam cells in the elicited peritoneal macrophage population. Analysis of macrophages from the above four experimental groups revealed massive reprogramming of the lipidome in response to both diet and genotype. These studies confirmed and extended prior knowledge regarding the roles of SREBP and LXR signaling in cholesterol and fatty acid homeostasis. Unexpectedly, peritoneal macrophage foam cells exhibited a strongly 'deactivated' phenotype, with marked suppression of pro-inflammatory mediators that are normally characteristic of the inflammatory responses associated with atherosclerotic lesions. Many of these changes in gene expression and lipid metabolism appear to be related to the paradoxical accumulation of high levels of desmosterol, the last intermediate in the Bloch pathway of cholesterol biosynthesis. WT or LDLR KO mice were fed either a NCNF diet or a HCHF diet for twelve weeks to establish four experimental groups (WT-NCNF diet, WT-HCHF diet, KO-NCNF diet, and KO-HCHF diet). As expected, the combination of the HCHF diet and LDLR KO genotype resulted in a synergistic effect on serum lipid levels. Elicited peritoneal macrophages (92-96% F4/80-positive) were immediately prepared for analysis, thereby preserving in vivo gene expression and lipid profiles. Macrophages derived from LDLR KO mice fed the HCHF diet contained nearly four-fold more total cholesterol than cells from WT mice fed the same diet. Quantitative analysis of 245 lipid species revealed significant changes in nearly all major lipid classes. Using a two-way ANOVA model, we found that 176 (72%) of the lipids analyzed were significantly affected by the HCHF diet, 133 (54%) by the LDLR KO genotype, and 114 (46%) by interactions between the HCHF diet and LDLR KO genotype. Many of the observed interactions (60%) were synergistic.
Institute
LIPID MAPS
DepartmentMultiple
LaboratoryMultiple
Last NameFahy
First NameEoin
Address9500 Gilman, La Jolla, CA, 92093, USA
Emailefahy@ucsd.edu
Phone858-534-4076
Submit Date2019-12-17
PublicationsSpann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, Reichart D, Fox JN, Shaked I, Heudobler D, Raetz CR, Wang EW, Kelly SL, Sullards MC, Murphy RC, Merrill AH Jr, Brown HA, Dennis EA, Li AC, Ley K, Tsimikas S, Fahy E, Subramaniam S, Quehenberger O, Russell DW, Glass CK. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell. 2012 Sep 28;151(1):138-52. doi: 10.1016/j.cell.2012.06.054. PMID: 23021221; PMCID: PMC3464914.
Analysis Type DetailGC-MS/LC-MS
Release Date2020-01-22
Release Version1
Eoin Fahy Eoin Fahy
https://dx.doi.org/10.21228/M83M5X
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Diet
SA0936808_4LDLR-KO High fat
SA0936818_2LDLR-KO High fat
SA0936828_1LDLR-KO High fat
SA0936838_5LDLR-KO High fat
SA0936848_3LDLR-KO High fat
SA0936858_6LDLR-KO High fat
SA0936868_9LDLR-KO High fat
SA0936878_8LDLR-KO High fat
SA0936888_7LDLR-KO High fat
SA0936897_5LDLR-KO Normal
SA0936907_4LDLR-KO Normal
SA0936917_6LDLR-KO Normal
SA0936927_3LDLR-KO Normal
SA0936937_9LDLR-KO Normal
SA0936947_2LDLR-KO Normal
SA0936957_8LDLR-KO Normal
SA0936967_7LDLR-KO Normal
SA0936977_1LDLR-KO Normal
SA0936986_4Wild type High fat
SA0936996_3Wild type High fat
SA0937006_1Wild type High fat
SA0937016_5Wild type High fat
SA0937026_2Wild type High fat
SA0937036_9Wild type High fat
SA0937046_6Wild type High fat
SA0937056_8Wild type High fat
SA0937066_7Wild type High fat
SA0937075_4Wild type Normal
SA0937085_2Wild type Normal
SA0937095_5Wild type Normal
SA0937105_3Wild type Normal
SA0937115_8Wild type Normal
SA0937125_1Wild type Normal
SA0937135_9Wild type Normal
SA0937145_7Wild type Normal
SA0937155_6Wild type Normal
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