小鼠血清代谢组遗传结构研究揭示羧酸酯酶是循环脂肪酸代谢的主要调控因子
Genetic architecture of the murine serum metabolome reveals carboxyl esterases as master regulators of circulating fatty acid metabolism
研究团队对 Diversity Outbred（DO）群体的 541 只小鼠血清进行质谱检测，在 240 种代谢物、561 种脂质、43 种 oxylipin 和 4,465 个 MS/MS 特征中共鉴定出 1,933 个代谢物数量性状位点（mQTL）。第 8、9、10、17 号染色体上的 QTL 热点分别对应不同的血清脂质、代谢物和类肽特征调控位点，其中第 8 号染色体的 Ces1 和 Ces2 基因簇与脂质、acylcarnitine 和 acyl-CoA 相关，第 17 号染色体的 MHC 与 C3 区域则与未靶向的类肽 MS/MS 特征相关。
来源：PLOS Genetics · journals.plos.org
by Gregory R. Keele, Travis Nemkov, Ariel M. Hay, Matthew Vincent, Callan O'Connor, Daniel Stephenson, Grier P. Page, James C. Zimring, Gary A. Churchill, Angelo D’Alessandro
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. QTL hotspots on chromosomes 8, 9, 10, and 17 implicated distinct loci in the regulation of serum lipids, metabolites, and peptide-like features. The chromosome 8 Ces1 and Ces2 gene clusters were associated with lipids, acylcarnitines, and acyl-CoAs, while chromosome 9 and 10 loci included additional lipid and metabolite QTL. On chromosome 17, MHC and C3 regions were associated with untargeted peptide-like MS/MS features. 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.