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Identification of pre-diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis – a nested case-control study within the ATBC cohort

ABSTRACT:

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR) < 0.05. A chemical set enrichment analysis (ChemRICH) and co-regulatory set analysis suggested that 22/28 lipid classes and 47/83 correlation modules were significantly associated with liver cancer risk (FDR < 0.05). Strong positive associations were observed for monounsaturated fatty acids (MUFA), triacylglycerols (TAGs), and phosphatidylcholines (PCs) having MUFA acyl chains. Negative associations were observed for sphingolipids (ceramides and sphingomyelins), lysophosphatidylcholines, cholesterol esters and polyunsaturated fatty acids (PUFA) containing TAGs and PCs. Stearoyl-CoA desaturase enzyme 1 (SCD1), a rate limiting enzyme in fatty acid metabolism and ceramidases seems to be critical in this reprogramming. In conclusion, our study reports pre-diagnostic lipid changes that provide novel insights into hepatic lipid metabolism reprogramming may contribute to a pro-cell growth and anti-apoptotic tissue environment and, in turn, support liver cancer initiation.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: Dinesh Barupal

PROVIDER: MTBLS7776 | MetaboLights | 2023-09-18

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS7776	Other
	FILES	Other
	a_MTBLS7776_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS7776_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	files-all.json	Other

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Project description:In this study, RNA-Seq technology was adopted to investigate the differences in expression profiles of the hepatic lipid metabolism-related genes and the associated pathways between juvenile and laying hens. RNA-Seq analysis was carried out to estimate total RNA harvested from the liver of juvenile hens (n = 3) and laying hens (n = 3). Compared with juvenile hens, 2574 differentially expressed (DE) genes (1487 down and 1087 up) with P â¤ 0.05 were obtained, and 955 of these genes were significantly DE (SDE) at a false discovery rate (FDR) of 0.05 and fold-change â¥ 2 in laying hens. There were 198 SDE novel genes (107 down-regulated and 91 up-regulated) (FDR â¤ 0.05) that were obtained from the transcriptome, and most of them were highly expressed. Moreover, 332 SDE isoforms were identified. Gene Ontology (GO) enrichment and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that SDE genes were significantly associated with steroid biosynthesis, PPAR signaling pathway, biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, three amino acid pathways, and pyruvate metabolism (P â¤ 0.05). The top significantly enriched GO terms included lipid biosynthesis, cholesterol and sterol metabolic, and oxidation reduction suggesting the principal lipogenesis in the liver of laying hens. This study suggests that the major changes at the level of transcriptome in laying hen liver are closely related to fat metabolism. Some highly differentially expressed uncharacterized novel genes and alternative splicing isoforms detected might also take part in lipid metabolism, though it needs investigation. Therefore, this study provides valuable information of mRNA of chicken liver, and deeper functional investigations on the mRNAs could help explore or provide new insights into molecular networks of lipid metabolism in chicken liver. The liver expression profile of juvenile hens and laying hens were generated by RNA-seq.

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Identification of pre-diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis – a nested case-control study within the ATBC cohort

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