Department of Medical Genetics, University of Cambridge, Cambridge, UK.
The Alan Turing Institute, London, UK.
Thorax. 2020 Aug;75(8):679-688. doi: 10.1136/thoraxjnl-2019-214241. Epub 2020 May 28.
Lymphangioleiomyomatosis (LAM) is a rare multisystem disease almost exclusively affecting women which causes loss of lung function, lymphatic abnormalities and angiomyolipomas. LAM occurs sporadically and in people with tuberous sclerosis complex (TSC). Loss of gene function leads to dysregulated mechanistic target of rapamycin (mTOR) signalling. As mTOR is a regulator of lipid and nucleotide synthesis, we hypothesised that the serum metabolome would be altered in LAM and related to disease severity and activity.
Ultrahigh performance liquid chromatography-tandem mass spectroscopy was used to examine the serum metabolome of 79 closely phenotyped women with LAM, including 29 receiving treatment with an mTOR inhibitor and 43 healthy control women.
Sphingolipid, fatty acid and phospholipid metabolites were associated with FEV in women with LAM (eg, behenoyl sphingomyelin adjusted (adj.) p=8.10 × 10). Those with higher disease-burden scores had abnormalities in fatty acid, phospholipid and lysolipids. Rate of loss of FEV was associated with differences in acyl-carnitine, acyl-glycines, acyl-glutamine, fatty acids, endocanbinoids and sphingolipids (eg, myristoleoylcarnitine adj. p=0.07). In TSC-LAM, rapamycin affected modules of interrelated metabolites which comprised linoleic acid, the tricarboxylic acid cycle, aminoacyl-tRNA biosynthesis, cysteine, methionine, arginine and proline metabolism. Metabolomic pathway analysis within modules reiterated the importance of glycerophospholipid metabolites (adj. p=0.047).
Women with LAM have altered lipid metabolism. The associations between these metabolites, multiple markers of disease activity and their potential biological roles in cell survival and signalling, suggest that lipid species may be both disease-relevant biomarkers and potential therapeutic targets for LAM.
淋巴管平滑肌瘤病（LAM）是一种罕见的多系统疾病，几乎仅影响女性，导致肺功能丧失、淋巴异常和血管平滑肌脂肪瘤。LAM 散发性发生，与结节性硬化症复合征（TSC）相关。基因功能丧失导致雷帕霉素靶蛋白（mTOR）信号通路失调。由于 mTOR 是脂质和核苷酸合成的调节剂，我们假设 LAM 及相关疾病的严重程度和活动与血清代谢组会发生改变。
使用超高效液相色谱-串联质谱法检测 79 名表型密切的 LAM 女性患者的血清代谢组，其中 29 名接受 mTOR 抑制剂治疗，43 名健康对照女性。
鞘脂、脂肪酸和磷脂代谢物与 LAM 女性的 FEV 相关（例如，二十二酰基鞘氨醇调整后（adj.）p=8.10×10）。疾病负担评分较高的患者存在脂肪酸、磷脂和溶血磷脂的异常。FEV 丧失率与酰基肉碱、酰基甘氨酸、酰基谷氨酰胺、脂肪酸、内卡林和鞘脂的差异相关（例如，豆蔻酰肉碱 adj. p=0.07）。在 TSC-LAM 中，雷帕霉素影响包含亚油酸、三羧酸循环、氨基酸酰基-tRNA 合成、半胱氨酸、蛋氨酸、精氨酸和脯氨酸代谢的相关代谢物模块。模块内代谢途径分析再次强调了甘油磷脂代谢物的重要性（adj. p=0.047）。
LAM 女性存在脂质代谢异常。这些代谢物与多种疾病活动标志物之间的关联及其在细胞存活和信号转导中的潜在生物学作用，表明脂质种类可能既是与疾病相关的生物标志物，也是 LAM 的潜在治疗靶点。
