Influence of SNPs in nutrient-sensitive candidate genes and gene–diet interactions on blood lipids: the DiOGenes study

Blood lipid response to a given dietary intervention could be determined by the effect of diet, gene variants or gene–diet interactions. The objective of the present study was to investigate whether variants in presumed nutrient-sensitive genes involved in lipid metabolism modified lipid profile after weight loss and in response to a given diet, among overweight European adults participating in the Diet Obesity and Genes study. By multiple linear regressions, 240 SNPs in twenty-four candidate genes were investigated for SNP main and SNP–diet interaction effects on total cholesterol, LDL-cholesterol, HDL-cholesterol and TAG after an 8-week low-energy diet (only main effect), and a 6-month ad libitum weight maintenance diet, with different contents of dietary protein or glycaemic index. After adjusting for multiple testing, a SNP–dietary protein interaction effect on TAG was identified for lipin 1 (LPIN1) rs4315495, with a decrease in TAG of − 0·26 mmol/l per A-allele/protein unit (95 % CI − 0·38, − 0·14, P= 0·000043). In conclusion, we investigated SNP–diet interactions for blood lipid profiles for 240 SNPs in twenty-four candidate genes, selected for their involvement in lipid metabolism pathways, and identified one significant interaction between LPIN1 rs4315495 and dietary protein for TAG concentration.

Association of lipoprotein lipase gene polymorphisms with obesity and type 2 diabetes in an Asian Indian population

AIMS: Lipoprotein lipase (LPL), a pivotal enzyme in lipoprotein metabolism, catalyzes the hydrolysis of triglycerides of very low-density lipoproteins and chylomicrons. Assuming that the variants in the promoter of the LPL gene may be associated with changes in lipid metabolism leading to obesity and type 2 diabetes, we examined the role of promoter variants (-T93G and -G53C) in the LPL gene in an urban South Indian population. METHODS: The study subjects (619 type 2 diabetic and 731 normal glucose-tolerant (NGT) subjects) were chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The polymorphisms were genotyped using polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. RESULTS: The two polymorphisms studied were not in LD. The -T93G was not associated with type 2 diabetes but was associated with obesity. 11.5% of the obese subjects (62/541) had the XG(TG+GG) genotype compared with 6.4% of the nonobese subjects (52/809; P=0.001). The odds ratio for obesity for the XG genotype was 1.766 (95% CI: 1.19-2.63, P=0.005). Subjects with XG genotype also had higher body mass index and waist circumference compared with those with TT genotype. With respect to G53C, subjects with the XC(GC+CC) genotype had 0.527 and 0.531 times lower risk for developing type 2 diabetes and obesity, respectively. CONCLUSIONS: Among Asian Indians, the -T93G SNP of the LPL gene is associated with obesity but not type 2 diabetes, whereas the -G53C SNP appears to be protective against both obesity and type 2 diabetes.

Potential anti-obesogenic properties of non-digestible carbohydrates: specific focus on resistant dextrin

Alterations in the composition and metabolic activity of the gut microbiota appear to contribute to the development of obesity and associated metabolic diseases. However, the extent of this relationship remains unknown. Modulating the gut microbiota with non-digestible carbohydrates (NDC) may exert anti-obesogenic effects through various metabolic pathways including changes to appetite regulation, glucose and lipid metabolism and inflammation. The NDC vary in physicochemical structure and this may govern their physical properties and fermentation by specific gut bacterial populations. Much research in this area has focused on established prebiotics, especially fructans (i.e. inulin and fructo-oligosaccharides); however, there is increasing interest in the metabolic effects of other NDC, such as resistant dextrin. Data presented in this review provide evidence from mechanistic and intervention studies that certain fermentable NDC, including resistant dextrin, are able to modulate the gut microbiota and may alter metabolic process associated with obesity, including appetite regulation, energy and lipid metabolism and inflammation. To confirm these effects and elucidate the responsible mechanisms, further well-controlled human intervention studies are required to investigate the impact of NDC on the composition and function of the gut microbiota and at the same time determine concomitant effects on host metabolism and physiology.

Apples and cardiovascular health: is the gut microbiota a core consideration?

There is now considerable scientific evidence that a diet rich in fruits and vegetables can improve human health and protect against chronic diseases. However, it is not clear whether different fruits and vegetables have distinct beneficial effects. Apples are among the most frequently consumed fruits and a rich source of polyphenols and fiber. A major proportion of the bioactive components in apples, including the high molecular weight polyphenols, escape absorption in the upper gastrointestinal tract and reach the large intestine relatively intact. There, they can be converted by the colonic microbiota to bioavailable and biologically active compounds with systemic effects, in addition to modulating microbial composition. Epidemiological studies have identified associations between frequent apple consumption and reduced risk of chronic diseases such as cardiovascular disease. Human and animal intervention studies demonstrate beneficial effects on lipid metabolism, vascular function and inflammation but only a few studies have attempted to link these mechanistically with the gut microbiota. This review will focus on the reciprocal interaction between apple components and the gut microbiota, the potential link to cardiovascular health and the possible mechanisms of action.

Transcriptome analysis for discovering candidate genes involve in embryogenesis in coconut (Cocos nucifera L.) through 454 pyrosequencing

Coconut, Cocos nucifera L. is a major plantation crop, which ensures income for millions of people in the tropical region. Detailed molecular studies on zygotic embryo development would provide valuable clues for the identification of molecular markers to improve somatic embryogenesis. Since there is no ongoing genome project for this species, coconut expressed sequence tags (EST) would be an interesting technique to identify important coconut embryo specific genes as well as other functional genes in different biochemical pathways. The goal of this study was to analyse the ESTs by examining the transcriptome data of the different embryo tissue types together with one somatic tissue. Here, four cDNA libraries from immature embryo, mature embryo, microspore derived embryo and mature leaves were constructed. cDNA was sequenced by the Roche-454 GS-FLX system and assembled into 32621 putative unigenes and 155017 singletons. Of these unigenes, 18651 had significant sequence similarities to non-redundant protein database, from which 16153 were assigned to one or more gene ontology categories. Homologue genes, which are responsible for embryo development such as chitinase, beta-1,3-glucanase, ATP synthase CF0 subunit, thaumatin-like protein and metallothionein-like protein were identified among the embryo EST collection. Of the unigenes, 6694 were mapped into 139 KEGG pathways including carbohydrate metabolism, energy metabolism, lipid metabolism, amino acid metabolism and nucleotide metabolism. This collection of 454-derived EST data generated from different tissue types provides a significant resource for genome wide studies and gene discovery of coconut, a non-model species.

Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production

Background: The hypocholesterolemic effects of soy foods are well established, and it has been suggested that isoflavones are responsible for this effect. However, beneficial effects of isolated isoflavones on lipid biomarkers of cardiovascular disease risk have not yet been shown. Objective: The objective was to investigate the effects of isolated soy isoflavones on metabolic biomarkers of cardiovascular disease risk, including plasma total, HDL, and LDL cholesterol; triacylglycerols; lipoprotein(a); the percentage of small dense LDL; glucose; nonesterified fatty acids; insulin; and the homeostasis model assessment of insulin resistance. Differences with respect to single nucleotide polymorphisms in selected genes [ie, estrogen receptor a (Xbal and PvuII), estrogen receptor beta (AluI), and estrogen receptor beta(cx) (Tsp5091), endothelial nitric oxide synthase (Glu298Asp), apolipoprotein E (Apo E2, E3, and E4), cholesteryl ester transfer protein (TaqIB), and leptin receptor (Gln223Arg)] and with respect to equol production were investigated. Design: Healthy postmenopausal women (n = 117) participated in a randomized, double-blind, placebo-controlled, crossover dietary intervention trial. Isoflavone-enriched (genistein-to-daidzein ratio of 2: 1; 50 mg/d) or placebo cereal bars were consumed for 8 wk, with a wash-out period of 8 wk before the crossover. Results: Isoflavones did not have a significant beneficial effect on plasma concentrations of lipids, glucose, or insulin. A significant difference between the responses of HDL cholesterol to isoflavones and to placebo was found with estrogen receptor 0(cx) Tsp5091 genotype AA, but not GG or GA. Conclusions: Isoflavone supplementation, when provided in the form and dose used in this study, had no effect on lipid or other metabolic biomarkers of cardiovascular disease risk in postmenopausal women but may increase HDL cholesterol in an estrogen receptor P gene-polymorphic subgroup.

Effects of consumption of probiotics and prebiotics on serum lipid levels in humans

The objective of this article is to review existing studies concerning the effects of probiotics and prebiotics on serum cholesterol concentrations, with particular attention on the possible mechanisms of their action. Although not without exception, results from animal and human studies suggest a moderate cholesterol-lowering action of dairy products fermented with appropriate strain(s) of lactic acid bacteria and bifidobacteria. Mechanistically, probiotic bacteria ferment food-derived indigestible carbohydrates to produce short-chain fatty acids in the gut, which can then cause a decrease in the systemic levels of blood lipids by inhibiting hepatic cholesterol synthesis and/or redistributing cholesterol from plasma to the liver. Furthermore, some bacteria may interfere with cholesterol absorption from the gut by deconjugating bile salts and therefore affecting the metabolism of cholesterol, or by directly assimilating cholesterol. For prebiotic substances, the majority of studies have been done with the fructooligosaccharides inulin and oligofructose, and although convincing lipid-lowering effects have been observed in animals, high dose levels had to be used. Reports in humans are few in number. In studies conducted in normal-lipidemic subjects, two reported no effect of inulin or oligofructose on serum lipids, whereas two others reported a significant reduction in serum triglycerides (19 and 27%, respectively) with more modest changes in serum total and LDL cholesterol. At present, data suggest that in hyperlipidemic subjects, any effects that do occur result primarily in reductions in cholesterol, whereas in normal lipidemic subjects, effects on serum triglycerides are the dominant feature.

Effects of lipid emulsions on lipid body formation and eicosanoid production by human peripheral blood mononuclear and polymorphonuclear cells

Background & aims: This study investigated the influence of four commercial lipid emulsions, Ivelip, ClinOleic, Omegaven and SMOFlipid (R), on lipid body formation, fatty acid composition and eicosanoid production by cultured human peripheral blood polymorphonuclear cells (PMN) and mononuclear cells (PBMC). Methods: PMN and PBMC were exposed to emulsions at concentrations ranging from 0.01 to 0.04%. Lipid body formation was assessed by microscopy, fatty acid composition by gas chromatography and eicosanoids by ELISA. Results: Stimulation of inflammatory cells and exposure to lipid emulsions promoted the formation of lipid bodies, but there did not appear to be differential effects of the emulsions tested. In contrast, there were differential effects of lipid emulsions on eicosanoid formation, particularly with regards to LTB4 production by PMN. Omegaven dramatically increased production of eicosanoids compared with the other emulsions in a dose-dependent manner. This effect was associated with a significantly higher level of lipid peroxides in the supernatants of cells exposed to Omegaven. Conclusions: Stimulation of inflammatory cells and exposure to lipid emulsions promotes lipid body formation and eicosanoid production, although the differential effects of different emulsions appear to be largely due to lipid peroxidation of unsaturated fatty acids in some emulsions in this in vitro system. (C) 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Gastrointestinal tract: intestinal fatty acid metabolism and implications for health

Short-chain fatty acids (SCFA) are formed from the fermentation of sugars by intestinal bacteria. Acetate is the most abundant SCFA, with lower amounts of propionate and butyrate formed. Propionate and butyrate are also formed from the products of carbohydrate fermentation by other bacteria, for example from lactate and acetate. SCFA play a role in regulating transit of digesta through the intestine, and butyrate formation is thought to be beneficial to health because butyrate decreases the risk of colon cancer. Major butyrate-producing species are among the most abundant present in the colon, including Roseburia and Faecalibacterium spp. Metabolism of longer-chain fatty acids occurs mainly by hydration or hydrogenation of unsaturated fatty acids. Hydroxystearic acids are formed in the intestine, particularly under disease conditions. Metabolism of linoleic acid results in the formation of conjugated linoleic acids (CLA) by several species, including Roseburia hominis and Roseburia inulinovorans. Enhancement of intestinal CLA formation, possibly using probiotics, may be useful in preventing or treating inflammatory bowel disease.

The impact of EPA and DHA on blood lipids and lipoprotein metabolism: influence of apoE genotype

Fish and fish oil-rich sources of long-chain n-3 fatty acids have been shown to be cardio-protective, through a multitude of different pathways including effects on arrythymias, endothelial function, inflammation and thrombosis, as well as modulation of both the fasting and postprandial blood lipid profile. To date the majority of studies have examined the impact of EPA and DHA fed simultaneously as fish or fish oil supplements. However, a number of recent studies have compared the relative biopotency of EPA v. DHA in relation to their effect on blood lipid levels. Although many beneficial effects of fish oils have been demonstrated, concern exists about the potential deleterious impact of EPA and DHA on LDL-cholesterol, with a highly-heterogenous response of this lipid fraction reported in the literature. Recent evidence suggests that apoE genotype may be in part responsible. In the present review the impact of EPA and DHA on cardiovascular risk and the blood lipoprotein profile will be considered, with a focus on the apoE gene locus as a possible determinant of lipid responsiveness to fish oil intervention.

Polyunsaturated fatty acids of the n-6 and n-3 series: effects on postprandial lipid and apolipoprotein levels in healthy men

OBJECTIVE: The present study was carried out to determine effects of test meals of different fatty acid compositions on postprandial lipoprotein and apolipoprotein metabolism. DESIGN: The study was a randomized, single blind design. SETTING: The study was carried out in the Clinical Investigation Unit of the Royal Surrey County Hospital. SUBJECTS: Twelve male normal subjects with an average age of 22.4 +/- 1.4 years (mean +/- SD) were selected from the student population of the University of Surrey; one subject dropped out of the study because he found the test meal unpalatable. INTERVENTIONS: The subjects were given three evening test meals on three separate occasions, in which the oils used were either a mixed oil (rich in saturated fatty acids and approximated the fatty acid intake of the current UK diet), corn oil (rich in n-6 fatty acids), or fish oil (rich in n-3 fatty acids) 40 g of the oil under investigation were incorporated into a rice-based test meal. Triacylglycerol-rich lipoproteins-triacylglycerol (TRL-TAG), TRL-cholesterol (TRL-cholesterol), plasma-TAG, plasma cholesterol (T-C), and serum apolipoprotein A-I and B (apo A-I and B) responses were measured. Postprandial responses were followed for 11 h. RESULTS: Postprandial plasma-TAG responses, calculated as incremental areas under the response curves (IAUC) were significantly reduced following the fish oil meal [365.5 +/- 145.4 mmol/l x min (mean +/- SD)[ compared with the mixed oil meal (552.0 +/- 141.7 mmol/l x min) (P < 0.05) and there was a strong trend towards the same direction in the TRL-TAG responses. In all instances, plasma-and TRL-TAG showed a biphasic response with increased concentrations occurring at 1h and between 3 and 7h postprandially. TRL-cholesterol, T-C, and serum apo A-I and B responses to the three meals were similar. CONCLUSIONS: The findings support the view that fish oils decrease postprandial lipaemia and this may be an important aspect of their beneficial effects in reducing risk of coronary heart disease (CHD). Further work is required to determine the mechanisms responsible for this effect.

Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.

The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle.