Dyslipidemia due to high total cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, or low high density lipoprotein (HDL)-cholesterol is an important risk factor for coronary heart disease (CHD) [1, 2]. Data from family and twin studies suggest that genetic variations account for 40-60% of the inter-individual variations in plasma lipid levels [2, 3]. In addition to rare mutations that cause familial dyslipidemia, common genetic variants are considered to significantly contribute to the heritability of plasma lipid levels. For example, genome-wide association studies (GWAS) have reported a growing number of new loci involved in lipid metabolism [4, 5]. However, loci identified through GWAS may not fully explain the inter-individual variation in plasma lipid levels.
Sirtuin 1 (SIRT1) belongs to the sirtuin protein family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases conserved in evolution from bacteria to humans [6, 7]. Human have seven sirtuin family members, SIRT1-SIRT7, which exhibit with different cellular locations, enzyme activities, target substrates and tissue-specificity. Of these, SIRT1 has been most extensively studied. SIRT1 is a nuclear protein and promotes chromatin silencing and transcriptional repression through histone deacetylation. In addition, more than a dozen non-histone proteins serve as substrates for SIRT1. SIRT1 controls numerous physiological processes and protects cells against stress. A number of studies have shown that SIRT1 orthologs are important mediators of the extension of life span observed from yeast to mammals following calorie restriction. During energy crises such as calorie restriction, NAD+ level rise, concomitant with SIRT1 activation [6, 7]. Transgenic mice overexpressing SIRT1 have beneficial calorie restriction-like phenotypes, while down-regulation of SIRT1 accelerates the aging phenotype in mice .
Furthermore, SIRT1 also has an important function in lipid and glucose metabolism, due to deacetylation of a number of nuclear receptors and transcription factors related to lipid and glucose metabolism such as peroxisome-proliferator activated receptor (PPAR)α, PPARγ, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α), liver X receptor (LXR)α, LXRβ, forkhead box O (FOXO), AMP-activated protein kinase (AMPK) and sterol response element-binding protein-1c (SREBP-1c) [6–11]. Thus, SIRT1 is associated with lipid metabolism, and variations of the SIRT1 gene might affect the determination of inter-individual variations of plasma lipid levels.
Fatty acids are no longer just sources of energy, but also fine modulators of cellular signaling and metabolism . There is growing evidence of health benefits of consuming certain types of fats including n-6 and n-3 polyunsaturated fatty acids (PUFAs)[12, 13], which are essential fatty acids that are not synthesized de novo by mammals. Several studies have shown that dietary intake of n-6 PUFAs, such as linoleic acid found in vegetable oils, may reduce CHD risk by beneficial effects on serum total cholesterol, LDL cholesterol, and insulin sensitivity , while n-3 PUFA derived from fish has also been shown to decrease serum triglyceride and increase HDL-cholesterol, which is associated with more efficient reverse cholesterol transport and a reduced risk of CHD [15, 16]. It is also reported that n-3 PUFA have anti-inflammatory effects . However, the cellular mechanisms underling the beneficial effects of n-6 and n-3 PUFA on lipid profile and CHD prevention are not completely understood. Recently, n-6 and n-3 PUFAs were shown to be critical for modulation of expression in several nuclear receptors and transcription factors, including LXRα, LXRβ, PPARα, SREBP-1c, hepatocyte nuclear factor (HNF)-4α, and nuclear factor-κB (NFκB) . The majority of these genes play key roles in lipid metabolism, and their expression is also modulated by SIRT1 [6–11]. Furthermore, it was reported that calorie restriction and dietary n-3 PUFA intake induce the similar beneficial effects such as anti-inflammation, preventing obesity and increasing expression insulin sensitivity in mice . Recently, it was shown that the anti-inflammatory effect of n-3 PUFAs might be mediated through activation of AMPK/SIRT1 pathways; because of n-3 PUFAs increased expression, phosphorylation and activity of AMPK in macrophages, which further leaded to SIRT1 over-expression . These data indicate the possibility that dietary n-3 PUFAs intake modify the SIRT1 activity in vivo.
In the present study, we investigated whether the common variations in the SIRT1 gene are potential contributors to inter-individual variations in serum lipid levels. Furthermore, we analyzed the interaction of the common SIRT1 variants and dietary n-3 and n-6 PUFAs intake on determination of serum lipid levels.