Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition

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 (GWAS)-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 3 FADS genes (FADS1, FADS2 and FADS3) in the locus was also investigated. We found that while 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 very-long-chain fatty acids (VLCFAs), 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 VLCFAs, 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.

Nonalcoholic Fatty Liver Disease

“…Only a minority of genes associated with NAFLD through candidate-gene analysis have been independently validated in large independent studies or through the use of transmission disequilibrium testing. This short list includes mitochondrial superoxide dismutase 2 (SOD2) 77 , phosphatidylethanolamine Nmethyltransferase (PEMT) 78 , fatty acid desaturase 1 79 and kruppel-like factor-6 (KLF6) 80 . All of these genes were associated with progressive NAFLD rather than NAFLD per se.…”

The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults

“…However, information on how factors, including n-3 PUFA intakes, health status and ethnicity, may influence the penetrance of the FADS genotype, and in turn the effect size, is relatively unknown. Further research, expanding on the recent research by Wang et al (26) , is also required to determine the functional SNP, as well the molecular mechanism(s) responsible for the effect of the FADS genotype on EPA and DHA status. Wang et al examined the association between six FADS SNP and the lipidomic profile and FADS1-3 expression in liver samples (n 154) and reported all six alleles to be associated with FADS1 (but not FADS2 and 3) gene expression and protein levels, suggesting that the causal variant(s) may be located at FADS1 (26) .…”

“…Further research, expanding on the recent research by Wang et al (26) , is also required to determine the functional SNP, as well the molecular mechanism(s) responsible for the effect of the FADS genotype on EPA and DHA status. Wang et al examined the association between six FADS SNP and the lipidomic profile and FADS1-3 expression in liver samples (n 154) and reported all six alleles to be associated with FADS1 (but not FADS2 and 3) gene expression and protein levels, suggesting that the causal variant(s) may be located at FADS1 (26) . In addition, twenty out of forty-two highly linked SNP Impact of FADS genotype on fatty acid status and cardiovascular health in adultswere located in the transcription factor-binding sites of the locus.…”

Fads1 and 2 are promoted to meet instant need for long-chain polyunsaturated fatty acids in goose fatty liver

“…Moreover, data from genome-wide association study and gene expression profiling as well as functional studies indicate that Fads1 is associated with cholesterol level and coronary artery disease [31], insulin resistance [32], and breast cancer [33], while Fads2 is associated with conditional change of skin, reproductive systems, and intestine [34,35], infant intelligence quotient [36], attention-deficit/hyperactivity disorder [37], breast cancer [33], and statin sensitivity [38]. Recently, Fads genes and their variants have been associated with multiple metabolic phenotypes in humans, that is, three Fads SNPs are not only associated with decreased hepatic expression of Fads1, but also associated with increased total hepatic fat content [39]. Additionally, it is found that Fads1 is reduced in human NAFLD [39].…”

“…Recently, Fads genes and their variants have been associated with multiple metabolic phenotypes in humans, that is, three Fads SNPs are not only associated with decreased hepatic expression of Fads1, but also associated with increased total hepatic fat content [39]. Additionally, it is found that Fads1 is reduced in human NAFLD [39]. Together, these findings suggest that Fads1 and its polymorphisms modulate hepatic lipid accumulation by altering gene transcription and lipid composition in human livers, and Fads1 may be a therapeutic target to human NAFLD.…”