Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition

Libo Wang, Shaminie Athinarayanan, Guanglong Jiang, Naga Chalasani, Min Zhang, Wanqing Liu

Research output: Contribution to journalArticle

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Abstract

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 of FADSs in 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 six FADS single-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 three FADS genes (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 of FADS1 (P=0.0018 for rs174556), but not FADS2 or FADS3 (P>0.05). Conclusion: Our findings revealed critical insight into the mechanism underlying FADS1 and its polymorphisms in modulating hepatic lipid deposition by altering gene transcription and controlling lipid composition in human livers.

Original languageEnglish
Pages (from-to)119-128
Number of pages10
JournalHepatology
Volume61
Issue number1
DOIs
StatePublished - Jan 1 2015

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Fatty Acid Desaturases
Lipids
Liver
Single Nucleotide Polymorphism
Genes
Fats
Sphingolipids
Ceramides
Genome-Wide Association Study
Linkage Disequilibrium
Phosphatidylinositols
Phospholipids
Fatty Acids
Alleles
Phenotype
Enzymes

ASJC Scopus subject areas

  • Hepatology

Cite this

Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition. / Wang, Libo; Athinarayanan, Shaminie; Jiang, Guanglong; Chalasani, Naga; Zhang, Min; Liu, Wanqing.

In: Hepatology, Vol. 61, No. 1, 01.01.2015, p. 119-128.

Research output: Contribution to journalArticle

Wang, L, Athinarayanan, S, Jiang, G, Chalasani, N, Zhang, M & Liu, W 2015, 'Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition', Hepatology, vol. 61, no. 1, pp. 119-128. https://doi.org/10.1002/hep.27373
Wang, Libo ; Athinarayanan, Shaminie ; Jiang, Guanglong ; Chalasani, Naga ; Zhang, Min ; Liu, Wanqing. / Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition. In: Hepatology. 2015 ; Vol. 61, No. 1. pp. 119-128.
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