A large-scale genome–lipid association map guides lipid identification

Abstract

Despite the crucial roles of lipids in metabolism, we are still at the early stages of comprehensively annotating lipid species and their genetic basis. Mass spectrometry(MS)-based discovery lipidomics offers the potential to globally survey lipids and their relative abundances in various biological samples. To discover the genetics of lipid features obtained through high resolution LC-MS/MS, we analyzed liver and plasma from 384 Diversity Outbred (DO) mice, and quantified 3,283 molecular features. These features were mapped to 5,622 lipid quantitative trait loci (QTL) and compiled into a public web-resource termed LipidGenie. This data is cross-referenced to the human genome and offers a bridge between genetic associations in humans and mice. Harnessing this resource, we used genome-lipid association data as an additional aid to identify a number of lipids, for example gangliosides through their association with B4galnt1 , and found evidence for a group of sex-specific phosphatidylcholines through their shared locus. Finally, LipidGenie’s ability to query either mass or gene-centric terms, suggests acyl chain-specific functions for proteins of the ABHD family.

AdipoAtlas: A reference lipidome for human white adipose tissue

“…Deep profiling of tissue-specific lipidomes is essential to support our understanding of human biology by elucidating not only tissue-/organ-specific lipid remodeling mechanisms, but also the cross-talk between different tissues, its impact on systemic regulation of the lipid metabolism, and genome-lipid associations. 41 In contrast to robust screening applications necessary for the analysis of large sample cohorts and potential clinical translation, deep lipidomics profiling of a particular tissue, organ, or cell type cannot be performed in a high-throughput manner and requires rigorous tissue-tailored optimizations and application of multiple orthogonal analytical workflows. Here, we provide the example of an analytical strategy targeting deep lipidomic profiling of human WAT, which can be transferred and adapted for the generation of reference lipidomes from any other human tissue.…”

Mitochondrial Lipid Signaling and Adaptive Thermogenesis

“…At the cellular level, several emerging technologies have led to higher lipid visualization and quantitation. Mass-spectrometry-based lipidomics has unearthed previously unidentified lipids including signaling molecules such as fatty acid esters of hydroxy fatty acids (FAHFAs), which regulate insulin sensitivity [ 89 , 90 ]. Chemical probes including photoswitches have the capacity to functionally characterize lipids and the proteins they interact with, while photocleavable groups can facilitate the temporal range of lipid activity [ 91 ].…”

Metabolomics and Lipidomics: Expanding the Molecular Landscape of Exercise Biology

“…In other mammalian species, recent efforts to utilize mouse genetic diversity panels and recombinant inbred mouse strains in metabolomics/lipidomics research have proven valuable tools for genetic mapping (i.e., quantitative trait loci mapping) and investigating environmental exposure, providing new insights into compound identification, as well as the molecular basis of metabolic health and disease. For example, a recent large-scale genome-lipid associated map and resource termed LipidGenie was generated by analysing liver and plasma samples from diversity outbred mice, which permitted the identification of unknown lipids from MS data by mapping molecular lipid features to genetic loci [ 158 ]. In addition, recombinant inbred mouse strains (e.g., ILSXISS) have been used to determine skeletal muscle metabolomic signatures reflective of IR across different mouse strains and diets [ 159 ].…”