Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition.
Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition.
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DOI：
10.1002/hep.27373
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发表时间：
2015-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Wanqing
中科院分区：
文献类型：
--
作者：
Wang, Libo;Athinarayanan, Shaminie;Jiang, Guanglong;Chalasani, Naga;Zhang, Min;Liu, Wanqing
脂肪酸去饱和酶（FADS）基因及其变异与多种代谢表型相关，包括肝酶和肝脏脂肪积累，但其具体机制尚不清楚。我们的目的是描述FADSs在调节人肝脏脂质组成中的作用。我们对154人肝组织样本中的多种磷脂、鞘脂和神经酰胺进行了针对性的脂质组学分析。之前的全基因组关联研究（GWAS）鉴定的6个FADS单核苷酸多态性（snp）与这些脂质水平以及肝总脂肪含量（HFC）之间的关系进行了测试。我们还研究了这些snp在调节FADS基因FADS1、FADS2和FADS3转录中的潜在功能。我们发现，虽然这些snp处于高度连锁不平衡状态（r2 >0.8），但这些snp的罕见等位基因与多种极长链脂肪酸（VLCFAs）的积累一致且显著相关，其中C47H85O13P (C36:4)，磷脂酰肌醇（PI）和C43H80O8PN (C38:3)，磷脂酰乙醇胺（PE）达到Bonferroni校正显著性（p<3×10−4）。同时，这些snp与饱和程度较高和相对不饱和程度较高的VLCFAs之间的比例增加显著相关，尤其是pe、pi和磷脂酰胆碱（PCs）之间的比例增加（p≤3.5×10−6）。这些等位基因也与总HFC升高相关（p<0.05）。进一步分析显示，这些等位基因与肝脏FADS1表达降低相关（rs174556的p=0.0018），但与FADS2或FADS3表达无关（p < 0.05）。我们的研究结果揭示了FADS1及其多态性通过改变基因转录和控制人类肝脏脂质组成来调节肝脏脂质沉积的机制。
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). 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.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
25.7
作者：
Allard, Johane P.;Aghdassi, Elaheh;Heathcote, Jenny E.
通讯作者：
Heathcote, Jenny E.
影响因子：
6.9
作者：
Guichelaar, M. M. J.;Gawrieh, S.;Olivier, M.;Viker, K.;Krishnan, A.;Sanderson, S.;Malinchoc, M.;Watt, K. D.;Swain, J. M.;Sarr, M.;Charlton, M. R.
通讯作者：
Charlton, M. R.
影响因子：
4.5
作者：
Innocenti F;Cooper GM;Stanaway IB;Gamazon ER;Smith JD;Mirkov S;Ramirez J;Liu W;Lin YS;Moloney C;Aldred SF;Trinklein ND;Schuetz E;Nickerson DA;Thummel KE;Rieder MJ;Rettie AE;Ratain MJ;Cox NJ;Brown CD
通讯作者：
Brown CD
DOI：
10.1073/pnas.0704292104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Caspi, Avshalom;Williams, Benjamin;Moffitt, Terrie E.
通讯作者：
Moffitt, Terrie E.