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This study analyzed the genetic regulation of blood metabolites in 541 genetically diverse mice, identifying nearly 2,000 genetic loci associated with 240 metabolites, 561 lipids, and other circulating compounds. The researchers discovered that carboxyl esterase gene clusters serve as major controllers of fatty acid and lipid metabolism in the bloodstream, and identified several genomic "hotspots" where multiple metabolic traits are regulated. The findings provide a detailed genetic map of metabolic regulation that complements human genetic studies by isolating genetic effects from environmental and lifestyle factors.
Why it matters
Understanding the genetic control of circulating metabolites could help identify therapeutic targets for metabolic diseases and explain individual differences in how people process fats and other nutrients. The discovery that carboxyl esterases are master regulators of fatty acid metabolism may lead to new approaches for treating conditions related to abnormal lipid metabolism.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background The systemic biochemical diversity of circulating metabolites and lipids reflects the integrated effects of genetic variation and environmental exposure. Metabolite quantitative trait locus (mQTL) studies in humans have established gene-metabolite associations, but genetic contributions can be obscured by sex, diet, age, medication use, and environmental exposures. Genetically diverse model systems offer a powerful complementary strategy to isolate genetic contributions to the biochemical diversity of the circulating metabolome. Methodology/Principal Findings We applied mass spectrometry profiling to serum samples in 541 mice from the Diversity Outbred (DO) population and identified 1,933 mQTL across 240 metabolites, 561 lipids, 43 oxylipins, and 4,465 MS/MS features. Co-mapping QTL, i.e., QTL hotspots, on chromosomes 8 and 17 implicated carboxyl esterase gene clusters (Ces1 and Ces2) as major regulators of circulating lipid remodeling and demonstrated genetic control of circulating protein/peptide-like features at the major histocompatibility complex and complement C3 loci. QTL hotspots on chromosomes 9 and 10 revealed previously unknown genetic drivers of lipid and amino acid metabolism. Comparisons with matched red blood cell mQTL revealed widespread compartment-specific genetic control. Conclusions/Significance Collectively, these findings provide a high-resolution map of the genetic regulation of the circulating metabolome, offering mechanistic insights that complement and extend human metabolic genetics.