Preliminary metabolomic and genomic exploration with gene-expression validation in multiple symmetric lipomatosis

Abstract

Abstract Background Multiple symmetric lipomatosis (MSL) is a rare disorder of fat metabolism with an incompletely understood pathogenesis and limited treatment options. This preliminary study explored metabolite differences and genomic characteristics in paired lesional and adjacent adipose tissues. Metabolome-genome association analysis and quantitative PCR (qPCR) follow-up were used to generate candidate molecular hypotheses. Methods Seven patients with multiple symmetric lipomatosis diagnosed from January 2022 to November 2023 were selected, and diseased tissues and adjacent normal adipose tissues were collected. Seven pairs of samples were subjected to nontargeted metabolomic analysis via ultraperformance liquid chromatography–high resolution mass spectrometry (UPLC–HRMS) to detect metabolites, and 5 pairs of samples were subjected to whole-genome sequencing to detect gene mutations. Finally, metabolomics‒genome association analysis was used to analyze the differentially expressed genes, and three pairs of samples were selected for validation via real-time quantitative PCR. Results A total of 977 metabolites, including 5-hydroxytryptophan (upregulated), threonine (downregulated) and aspartic acid (downregulated), were detected, and 42 differentially abundant metabolites (18 upregulated and 24 downregulated) were identified. The differentially abundant metabolites were enriched mainly in pathways related to glycerophospholipid metabolism, autophagy, and biosynthesis of glycosylphosphatidylinositol anchors; 2,915 candidate SNP sites were identified, and a total of 1,804 mutated genes were annotated. A total of 9 differentially expressed genes were identified, and compared with those in normal adipose tissues, CD200, MYF5, p107, IL4I1, and Cbl-b were upregulated in the lesion tissues of multifocal symmetric lipomatosis patients, and LIPE was significantly upregulated. The mRNA expression levels of UCP-1, CIDEA, and MFN2 were significantly decreased. Conclusions This preliminary analysis prioritized IL4I1 through mGWAS and identified gene-expression patterns consistent with differences in adipose phenotype, lipid metabolism, insulin signaling and mitochondrial function. Because the metabolomic, genomic and qPCR analyses included seven, five and three paired samples, respectively, these findings are hypothesis-generating and require independent validation.

The authors' abstract, as published at the source. Orphanet Journal of Rare Diseases, 2026 · DOI ↗