Fattyaciddesaturase 1gene polymorphisms control human hepatic lipid composition

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Fatty acid desaturase(FADS) genes and their variants have been associated with multiple metabolic phenotypes, including liver enzymes and hepatic fat accumulation, but the detailed mechanism remains unclear. We aimed to delineate the role ofFADSsin modulating lipid composition in human liver. We performed a targeted lipidomic analysis of a variety of phospholipids, sphingolipids, and ceramides among 154 human liver tissue samples. The associations between previously genome-wide association studies (GWASs)-identified sixFADSsingle-nucleotide polymorphisms (SNPs), and these lipid levels as well as total hepatic fat content (HFC) were tested. The potential function of these SNPs in regulating transcription of threeFADSgenes (FADS1,FADS2,and FADS3) in the locus was also investigated. We found that though these SNPs were in high linkage disequilibrium (r2 > 0.8), the rare alleles of these SNPs were consistently and significantly associated with the accumulation of multiple long-chain fatty acids (LCFAs), with C47H85O13P (C36:4), a phosphatidylinositol (PI), and C43H80O8PN (C38:3), a phosphatidylethanolamine (PE), reached the Bonferroni corrected significance (P< 3 × 10−4). Meanwhile, these SNPs were significantly associated with increased ratios between the more saturated and relatively less saturated forms of LCFAs, especially between PEs, PIs, and phosphatidylcholines (PCs;P≤ 3.5 × 10−6). These alleles were also associated with increased total HFC (P< 0.05). Further analyses revealed that these alleles were associated with decreased hepatic expression ofFADS1(P= 0.0018 for rs174556), but notFADS2orFADS3(P> 0.05).Conclusion: Our findings revealed critical insight into the mechanism underlyingFADS1and its polymorphisms in modulating hepatic lipid deposition by altering gene transcription and controlling lipid composition in human livers. (Hepatology 2015;61:119–128)

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