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Using integrative lipid systems biology to understand the role of Liver X receptor in male reproduction.
Jarvis S1,  Gethings LA2, Gadaleta RM1,3, Claude E2, Winston RML1, Williamson C4, Bevan CL1.


1Dept of Surgery and Cancer, Imperial College, Hammersmith Hospital London, UK 2Waters Corporation, Wilmslow, UK 3 4 Interdisciplinary Department of Medicine, University Hospital of Bari, Italy 4Department of Women and Children’s Health, Kings College London, Guys Campus, London, UK



Introduction: Liver-X receptors (LXRs) are transcription factors that regulate cholesterol homeostasis and are likely to modulate other aspects of lipid metabolism. In the testis, tightly regulated lipid metabolism is crucial to maintain fertility. Testicular LXRs are highly expressed in this tissue but their role in regulating lipid homeostasis is not fully understood. The Lxrα/β double knockout male mouse (Lxrα/β DKO) is sterile by 7 months of age, and develops aberrations in lipid metabolism.


Aim: To identify specific disrupted cellular lipids and likely candidate target genes in the testes of Lxrα/β DKO mice using wide platform integrated studies.


Methods: RNA-seq, quantitative mass spectrometry and mass spectrometry imaging (MSI) were combined to study whole testicular tissues from Lxrα/β DKO mice. cDNA libraries were prepared with sequencing using NextSeq-500.Lipid extracts were prepared LC-MS analysis with SONAR acquisition, based on an m/z isolation range of the quadrupole. Results were analysed using LipidMaps and Progenesis QI for normalized quantitation. For MSI, MALDI SYNAPT G2-Si (Waters) mass spectrometer was equipped with an ion mobility cell and experiments performed using Waters High Definition Imaging (HDI) 1.4 and MassLynx.


Results: Histological assessment of testicular tissues confirmed abnormal seminiferous tubules, germ-cell loss and lipid deposition in Lxrα/β DKO mice. Quantitative lipidomic analysis confirmed statistically significant differences in lipid species (including triglycerides, cholesterol esters and sphingolipids). Retrieved curated targets were mapped with KEGG pathway analysis. Alterations in cholesterol biosynthesis, triglyceride, sphingomyelin and ceramide metabolism were identified. From RNA-seq, 1161 genes (log2 FC -3.49 to +2.17, p<0.01) were differentially expressed in the Lxrα/β DKO with genes relevant to pathways identified from lipidomic data. Finally MSI confirmed deposition of specific lipid species and a visualization of their location in the testis.


Discussion: An integrative approach using lipidomic analysis with mRNA transcript studies provides data implicating LXRs in novel lipid pathways, critical for male reproductive function.