Human nutrigenomics of gene regulation by dietary fatty acids

Nutrigenomics employs high-throughput genomics technologies to unravel how nutrients modulate gene and protein expression and ultimately influence cellular and organism metabolism. The most often-applied genomics technique so far is transcriptomics, which allows quantifying genome-wide changes in gene expression of thousands of genes at the same time in one sample. The performance of gene expression quantification requires sufficient high-quality homogenous cellular material, therefore research in healthy volunteers is restricted to biopsies from easy accessible tissues such as subcutaneous adipose tissue, skeletal muscle and intestinal biopsies or even more easily accessible cells such as peripheral blood mononuclear cells from blood. There is now significant evidence that fatty acids, in particular unsaturated fatty acids, exert many of their effects through modulation of gene transcription by regulating the activity of numerous transcription factors, including nuclear receptors such as peroxisome proliferator activated receptors, liver X receptor and sterol regulatory binding proteins. This review evaluates the human nutrigenomics studies performed on dietary fat since the initiation of nutrigenomics research around 10 years ago. Although the number of studies is still limited, all studies clearly suggest that changes in dietary fatty acids intake and composition can have a significant impact on cellular adaptive response capacity by gene transcription changes in humans. This adds important knowledge to our understanding of the strong effects that various fatty acids can have on numerous metabolic and inflammatory pathways, signaling routes and homeostatic control in the cell and ultimately on whole body health. It is important to use and integrate nutrigenomics in all future nutrition studies to build up the necessary framework for evidence-based nutrition in near future

Fasting induces changes in peripheral blood mononuclear cell gene expression profiles realted to increases in fatty acid ß-oxidation: functional role of peroxisome proliferator-activated receptor alpha in human peripheral blood mononuclear cells 1-3

Background: Peripheral blood mononuclear cells (PBMCs) are the only readily available cells in healthy humans. Various studies showed disease-characteristic gene expression patterns in PBMCs. However, little is known of nutritional effects on PBMC gene expression patterns. Fatty acids are nutrients that regulate gene expression by activating the nuclear receptor peroxisome proliferator¿activated receptor (PPAR). PBMCs express PPAR, making these cells interesting to study FA-dependent gene expression. Objective: The aim of this study was to elucidate whether PBMC gene expression profiles also reflect nutrition-related metabolic changes. Furthermore, we focused on the specific role of PPAR in regulation of PBMC gene expression during fasting, when plasma free fatty acids are elevated. Design: Four healthy male volunteers fasted for 48 h. PBMC RNA was hybridized on Affymetrix whole genome microarrays. To elucidate the role of PPAR, PBMCs of 9 blood donors were incubated with the specific PPAR ligand Wy14643. Results: After 24 and 48 h of fasting, 1200 and 1386 genes were changed >1.4-fold, respectively. Many of those genes were involved in fatty acid ß-oxidation and are known PPAR target genes. Incubation of PBMCs with Wy14643 resulted in up-regulation of genes that were also up-regulated during fasting. Conclusions: We conclude that PBMC gene expression profiles reflect nutrition-related metabolic changes such as fasting and that part of the fasting-induced changes are likely regulated by PPAR

The H475Y polymorphism in the glutamate carboxypeptidase II gene increases plasma folate without affecting the risk for neural tube defects in humans.

In the diet, folate exists predominantly in the form of polyglutamates. Before absorption, these polyglutamates must be deconjugated to monoglutamates by the enzyme folylpoly-gamma-glutamate carboxypeptidase (FGCP), which is located in the jejunum. Recently, a H475Y polymorphism in the glutamate carboxypeptidase II (GCPII) gene, encoding the FGCP enzyme, was reported to be associated with decreased plasma folate and increased plasma homocysteine (tHcy) levels. Low folate and elevated tHcy levels are risk factors for neural tube defects (NTD). Therefore, we examined whether this polymorphism is associated with NTD risk and plasma folate, erythrocyte folate and plasma tHcy levels in 96 NTD patients, 113 mothers, 97 fathers and 101 controls. This variation was associated with increased plasma folate (P < 0.04) and tended to be associated with decreased plasma tHcy (P < 0.09). It was not associated with erythrocyte folate or the risk for NTD. The H475Y polymorphism in the GCPII gene may increase the deconjugation activity of the FGCP enzyme, resulting in an increased absorption of folate in the body, as reflected by the increased plasma folate and decreased plasma homocysteine concentrations

Nutritional aspects of metabolic inflammation in relation to health-insights from transcriptomic biomarkers in PBMC of fatty acids and polyphenols

Recent research has highlighted potential important interaction between metabolism and inflammation, within the context of metabolic health and nutrition, with a view to preventing diet-related disease. In addition to this, there is a paucity of evidence in relation to accurate biomarkers that are capable of reflecting this important biological interplay or relationship between metabolism and inflammation, particularly in relation to diet and health. Therefore the objective of this review is to highlight the potential role of transcriptomic approaches as a tool to capture the mechanistic basis of metabolic inflammation. Within this context, this review has focused on the potential of peripheral blood mononuclear cells transcriptomic biomarkers, because they are an accessible tissue that may reflect metabolism and subacute chronic inflammation. Also these pathways are often dysregulated in the common diet-related diseases obesity, type 2 diabetes, and cardiovascular disease, thus may be used as markers of systemic health. The review focuses on fatty acids and polyphenols, two classes of nutrients/nonnutrient food components that modulate metabolism/inflammation, which we have used as an example of a proof-of-concept with a view to understanding the extent to which transcriptomic biomarkers are related to nutritional status and/or sensitive to dietary interventions. We show that both nutritional components modulate inflammatory markers at the transcriptomic level with the capability of profiling pro- and anti-inflammatory mechanisms in a bidirectional fashion; to this end transcriptomic biomarkers may have potential within the context of metabolic inflammation. This transcriptomic biomarker approach may be a sensitive indicator of nutritional status and metabolic health

Disentangling the Effects of Monounsaturated Fat From Other Components of a Mediterranean Diet on Serum Metabolite Profiles: A Randomized Fully Controlled Dietary Intervention in Healthy Subjects at Risk of The Metabolic Syndrome

Scope The Mediterranean (MED) diet is considered to be beneficial, however the contribution of the MUFA component in these beneficial effects is unclear. Therefore, we wanted to disentangle the effects of MUFA from the other components in a MED diet. Methods and Results We performed a randomized fully controlled parallel trial to examine the effects of the consumption of a saturated fatty acid (SFA)‐rich diet, a MUFA‐rich diet, or a MED diet for eight weeks on serum metabolome, in 47 subjects at risk of the metabolic syndrome. We assessed 162 serum metabolites before and after the intervention, by using a targeted NMR platform. 52 metabolites were changed during the intervention (FDR p<0.05). Both MUFA and MED diet decreased exactly the same fractions of LDL, including particle number, lipid, phospholipid and free cholesterol fraction (FDR p <0.05). The MED diet additionally decreased the larger subclasses of VLDL, several related VLDL fractions, VLDL‐triglycerides, and serum‐triglycerides (FDR p<0.05). Conclusion Our findings clearly demonstrate that the MUFA component is responsible for reducing several LDL subclasses and fractions, and therefore causes a more anti‐atherogenic lipid profile. Interestingly, consumption of the other components in the MED diet show additional health effects. This trial was registered at clinicaltrials.gov as NCT00405197

Phenotyping the effect of diet on non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is associated with the growing incidence of metabolic syndrome. Diet is an important contributor to the pathogenesis of NAFLD. In this review, we focused on recent publications reporting on the effect of macro- and micronutrients on development and progression of NAFLD. In general, saturated fat and fructose seem to stimulate hepatic lipid accumulation and progression into NASH, whereas unsaturated fat, choline, antioxidants, and high-protein diets rich in isoflavones seem to have a more preventive effect. Knowledge of the underlying mechanisms by which diet affects NAFLD is expanding, not in the least due to innovative techniques, such as genomics tools that provide detailed comprehensive information on a large high-throughput scale. Although most nutrients seem to interfere with the balance between hepatic de novo lipogenesis (endogenous synthesis of fatty acids) and lipid oxidation (burning fat for energy), there are also indications that diet can trigger or prevent hepatic lipid accumulation by influencing the interaction between liver, gut, and adipose tissue. This review now gives a current detailed overview of diet-mediated mechanisms underlying NAFLD development and progression and summarizes recent results of genomics (transcriptomics, proteomics and metabolomics) studies that contribute to improved staging, monitoring and understanding of NAFLD pathophysiology

Gene-gene interaction between the cystathionine beta-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C &gt; T polymorphism on homocysteine levels and risk for neural tube defects.

Item does not contain fulltextINTRODUCTION: Most studies showed that mothers of children with NTD have elevated homocysteine levels pointing to a disturbed homocysteine metabolism as a risk factor for NTD. Folate lowers homocysteine levels by remethylation of homocysteine to methionine. Homocysteine can be irreversibly converted to cystathionine by the vitamin B6-dependent enzyme CBS. Recently, our group showed that a 31 bp VNTR in the CBS gene was associated with decreased CBS activity and increased tHcy levels after methionine loading in a CVD population. AIM: The aim of our study was to investigate whether this VNTR influences tHcy levels and risk for NTD. In addition, we assessed the role of vitamin B6 as an effect modifier in this possible interaction. We examined possible gene-gene interaction with the MTHFR 677C &gt; T polymorphism. We screened genomic DNA of 88 NBD patients, 100 mothers, 88 fathers, and 505 controls for this CBS 31 bp VNTR. RESULTS: In this study population five different alleles with 16,17, 18, 19, and 21 times the 31 bp repeat were observed that constituted 10 different genotypes. The most common 18/18 VNTR genotype was associated with higher tHcy levels compared with the 17/18 and 18/19 VNTR genotypes. Vitamin B6 levels did not influence this association. In addition, no association with risk for NTD was found. Combination of the CBS VNTR with the MTHFR 677C &gt; T polymorphism revealed an additional increase in homocysteine levels in 18-18 individuals compared with 17-18 peers within subjects homozygous mutant for the MTHFR 677C &gt; T polymorphism. CONCLUSIONS: The present study indicates that the number of 31 bp repeat elements in the CBS gene influences tHcy levels. This VNTR seems not to be associated with an increased risk for NTD

Dietary medium-chain saturated fatty acids induce gene expression of energy metabolism-related pathways in adipose tissue of abdominally obese subjects

Background:Dietary medium-chain saturated fatty acids (MC-SFAs) have been shown to reduce total body fat. Previously, we showed that MC-SFAs prevent body fat accumulation, despite weight gain. Here, we aim to explore potential molecular mechanisms underlying the protective effect of MC-SFAs on body fat gain.Methods:The DairyHealth study examined the long-Term effects of milk protein and milk fat with a low or high content of MC-SFA. In this 12 week, randomized, double-blind, diet intervention study, participants consumed 60 g milk protein (whey or casein) and 63 g milk fat (high MC-SFA or low MC-SFA) daily in a two by two factorial design. We used microarrays to measure whole genome gene expression changes in subcutaneous adipose tissue in a subpopulation of 12 participants, 6 in the low MC-SFA+casein group and 6 in the high MC-SFA+casein group. Gene expression of several genes that were found to be changed by MC-SFAs was confirmed in the full study population using qPCR.Results:High MC-SFA resulted in an upregulation of gene expression related to citric acid cycle and oxidative phosphorylation, and a downregulation of gene expression related to complement system and inflammation.Conclusions:We hypothesize that the beneficial effects of MC-SFAs on prevention of fat accumulation are mediated via increased gene expression related to energy metabolism in the adipose tissue. Decreases in inflammation-related gene expression may have beneficial effects in relation to cardiometabolic diseases