A network approach to micronutrient genetics: interactions with lipid metabolism.

PURPOSE OF REVIEW Although interactions between fat soluble micronutrients and lipid metabolism in relation to absorption, status and body composition have been well described, there is new evidence to suggest that key genes have profound effects on how micronutrients and lipids are handled in a range of cells and organs. This review highlights the importance of genetic variation in folate, selenium, zinc and carotenoid metabolism and the recent findings of micro-macro nutrient interactions. RECENT FINDINGS Although the methylenetetrahydrofolate reductase gene has been linked to CVD for some time, recent findings indicate that single-nucleotide polymorphisms (SNPs) in this gene are also linked to diabetes and may influence the pathogenesis of this disease through elevated alanine amino transferase concentrations. A recent selenium supplementation trial showed that SNPs can affect responses of GPx4, GPx1 and GPx3 protein expression or activity in response to Se supplementation or withdrawal. There is convincing evidence to suggest that the high variability of plasma carotenoids seen in human populations is at least partly caused by multiple genetic variations in genes involved in lipoprotein metabolism and lipid transfer. The most striking evidence of an interaction between carotenoid and lipid metabolism, however, comes from the observation that BCMO1 mice develop liver steatosis independent of the vitamin A content of the diet, and the discovery of common SNPs in this gene indicates that this interaction might be of clinical significance. SUMMARY Knowledge of genetic variants that affect micronutrient metabolism and responses to micronutrient supplementation were until recently largely limited to methylenetetrahydrofolate reductase. However, identification of novel functional SNPs in BCMO1, the critical enzyme of beta-carotene metabolism, and in several key selenoproteins indicates the potential importance of micronutrient-gene interactions.

[1]  A. Clifford,et al.  Dual isotope test for assessing β-carotene cleavage to vitamin A in humans , 2002 .

[2]  G. Siest,et al.  The Lipoprotein Lipase Serine 447 Stop Polymorphism Is Associated With Altered Serum Carotenoid Concentrations in the Stanislas Family Study , 2007, Journal of the American College of Nutrition.

[3]  F. Tchantchou,et al.  Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: Modulation by apolipoprotein E-deficiency , 2006, Nutritional neuroscience.

[4]  E. Reboul,et al.  Lycopene absorption in human intestinal cells and in mice involves scavenger receptor class B type I but not Niemann-Pick C1-like 1. , 2008, The Journal of nutrition.

[5]  J. Mathers,et al.  Evidence that a polymorphism within the 3′UTR of glutathione peroxidase 4 is functional and is associated with susceptibility to colorectal cancer , 2007, Genes & Nutrition.

[6]  S. Tsai,et al.  Cooperation between MEF2 and PPARγ in human intestinal β,β-carotene 15,15'-monooxygenase gene expression , 2006, BMC Molecular Biology.

[7]  U. Vogel,et al.  Associations between GPX 1 Pro 198 Leu polymorphism , erythrocyte GPX activity , alcohol consumption and breast cancer risk in a prospective cohort study , 2006 .

[8]  G. Duthie,et al.  Modulation of glutathione peroxidase activity in human vascular endothelial cells by fatty acids and the cytokine interleukin-1 beta. , 1996, Biochimica et biophysica acta.

[9]  A. Luke,et al.  Distribution and functional consequences of nucleotide polymorphisms in the 3'-untranslated region of the human Sep15 gene. , 2001, Cancer research.

[10]  D. Leclerc,et al.  Génétique moléculaire de MTHFR : Les polymorphismes ne sont pas tous bénins , 2007 .

[11]  P. Schneider,et al.  Method for the simultaneous determination of retinol and beta-carotene concentrations in human tissues and plasma. , 2002, Analytical biochemistry.

[12]  N. Plesnila,et al.  Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. , 2008, Cell metabolism.

[13]  R. Testa,et al.  +647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications. , 2008, Molecular genetics and metabolism.

[14]  E. Weeber,et al.  Deletion of Apolipoprotein E Receptor-2 in Mice Lowers Brain Selenium and Causes Severe Neurological Dysfunction and Death When a Low-Selenium Diet Is Fed , 2007, The Journal of Neuroscience.

[15]  P. Starostik,et al.  A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency , 2002, European Journal of Human Genetics.

[16]  K. Elliott,et al.  Genetic variation in selenoprotein S influences inflammatory response , 2005, Nature Genetics.

[17]  J. Mathers,et al.  Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender‐specific manner (the SELGEN study) , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  D. Morel,et al.  Carotenoid uptake and secretion by CaCo-2 cells: beta-carotene isomer selectivity and carotenoid interactions. , 2002, Journal of lipid research.

[19]  Vadim N. Gladyshev,et al.  How Selenium Has Altered Our Understanding of the Genetic Code , 2002, Molecular and Cellular Biology.

[20]  D. Lairon,et al.  Lutein transport by Caco-2 TC-7 cells occurs partly by a facilitated process involving the scavenger receptor class B type I (SR-BI). , 2005, The Biochemical journal.

[21]  Jack A. Taylor,et al.  Lycopene Intake and Prostate Cancer Risk: Effect Modification by Plasma Antioxidants and the XRCC1 Genotype , 2006, Nutrition and cancer.

[22]  N. Krinsky,et al.  Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses. , 2007, Molecular endocrinology.

[23]  R. Burk,et al.  Selenoprotein P: an extracellular protein with unique physical characteristics and a role in selenium homeostasis. , 2005, Annual review of nutrition.

[24]  D. Lairon,et al.  Human plasma levels of vitamin E and carotenoids are associated with genetic polymorphisms in genes involved in lipid metabolism. , 2007, The Journal of nutrition.

[25]  U. Vogel,et al.  GPX1 Pro198Leu polymorphism, interactions with smoking and alcohol consumption, and risk for lung cancer. , 2007, Cancer letters.

[26]  M. Abid,et al.  Hyperhomocysteinemia and elevated ox-LDL in Tunisian type 2 diabetic patients: role of genetic and dietary factors. , 2007, Clinical biochemistry.

[27]  K. Kohara,et al.  Replication Study of Candidate Genes Associated With Type 2 Diabetes Based On Genome-Wide Screening , 2009, Diabetes.

[28]  T. Sunderland,et al.  Regulation of the selenoprotein SelS by glucose deprivation and endoplasmic reticulum stress – SelS is a novel glucose‐regulated protein , 2004, FEBS letters.

[29]  R. Guigó,et al.  Characterization of Mammalian Selenoproteomes , 2003, Science.

[30]  A. Barua,et al.  beta-carotene is converted primarily to retinoids in rats in vivo. , 2000, The Journal of nutrition.

[31]  A. Loktionov.  Common gene polymorphisms and nutrition: emerging links with pathogenesis of multifactorial chronic diseases (review). , 2003, The Journal of nutritional biochemistry.

[32]  D. Lairon,et al.  Human fasting plasma concentrations of vitamin E and carotenoids, and their association with genetic variants in apo C-III, cholesteryl ester transfer protein, hepatic lipase, intestinal fatty acid binding protein and microsomal triacylglycerol transfer protein. , 2008, The British journal of nutrition.

[33]  R. Russell,et al.  Short-term (intestinal) and long-term (postintestinal) conversion of beta-carotene to retinol in adults as assessed by a stable-isotope reference method. , 2003, The American journal of clinical nutrition.

[34]  Brian L. Lindshield,et al.  Lycopene biodistribution is altered in 15,15'-carotenoid monooxygenase knockout mice. , 2008, The Journal of nutrition.

[35]  A. Clifford,et al.  Dual isotope test for assessing beta-carotene cleavage to vitamin A in humans. , 2002, European journal of nutrition.

[36]  J. C. Smith,et al.  Plasma carotenoids in normal men after a single ingestion of vegetables or purified beta-carotene. , 1989, The American journal of clinical nutrition.

[37]  J. Hesketh.  Nutrigenomics and selenium: gene expression patterns, physiological targets, and genetics. , 2008, Annual review of nutrition.

[38]  M. Tockman,et al.  Gene-environment interactions between the codon 194 polymorphism of XRCC1 and antioxidants influence lung cancer risk. , 2003, Anticancer research.

[39]  M. Malavolta,et al.  Zinc–gene interaction related to inflammatory/immune response in ageing , 2008, Genes & Nutrition.

[40]  Christine M. Williams,et al.  Personalised nutrition: status and perspectives , 2007, British Journal of Nutrition.

[41]  J. Kyle,et al.  A novel single nucleotide polymorphism in the 3' untranslated region of human glutathione peroxidase 4 influences lipoxygenase metabolism. , 2002, Blood cells, molecules & diseases.

[42]  E. Harrison,et al.  Xanthophylls are preferentially taken up compared with beta-carotene by retinal cells via a SRBI-dependent mechanism. , 2008, Journal of lipid research.

[43]  J. Berger,et al.  Retinaldehyde represses adipogenesis and diet-induced obesity , 2007, Nature Medicine.

[44]  Benito P Damasceno,et al.  Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene: A Novel Risk Factor for Arterial Ischemic Stroke Among Young Adults and Children , 2007, Stroke.

[45]  P. Bowen,et al.  Variability of Serum Carotenoids in Response to Controlled Diets Containing Six Servings of Fruits and Vegetables per Day , 1993, Annals of the New York Academy of Sciences.

[46]  K. Mochizuki,et al.  Regulation of cellular retinol-binding protein type II gene expression by arachidonic acid analogue and 9-cis retinoic acid in caco-2 cells. , 1999, European journal of biochemistry.

[47]  J. Ordovás.  Nutrigenetics, plasma lipids, and cardiovascular risk. , 2006, Journal of the American Dietetic Association.

[48]  Paul Haggarty,et al.  B-vitamins, genotype and disease causality* , 2007, Proceedings of the Nutrition Society.

[49]  T. Frayling,et al.  New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function , 2008, Current opinion in clinical nutrition and metabolic care.

[50]  J. Arthur,et al.  Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants. , 2003, Atherosclerosis.

[51]  U. de Faire,et al.  Phenotype determination of a common Pro-Leu polymorphism in human glutathione peroxidase 1. , 2000, Blood cells, molecules & diseases.

[52]  E. Harrison,et al.  Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. , 2005, The Journal of nutrition.

[53]  W. Blaner,et al.  In vitro and in vivo characterization of retinoid synthesis from beta-carotene. , 2008, Archives of biochemistry and biophysics.

[54]  D. Hunter,et al.  Gene × Gene interaction between MnSOD and GPX-1 and breast cancer risk: a nested case-control study , 2006, BMC Cancer.

[55]  J. Hesketh,et al.  Two common single nucleotide polymorphisms in the gene encoding β‐carotene 15,15′‐monoxygenase alter β‐carotene metabolism in female volunteers , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[56]  R. Rozen,et al.  [Molecular genetics of MTHFR: polymorphisms are not all benign]. , 2007, Medecine sciences : M/S.

[57]  U. Vogel,et al.  Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study. , 2006, Carcinogenesis.

[58]  Roy Taylor,et al.  Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause , 2008, Diabetologia.

[59]  J. Mathers,et al.  Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene: interaction with sex. , 2008, The American journal of clinical nutrition.

[60]  J. Amengual,et al.  CMO1 Deficiency Abolishes Vitamin A Production from β-Carotene and Alters Lipid Metabolism in Mice* , 2007, Journal of Biological Chemistry.

[61]  B. Ponder,et al.  Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  J. Guilland,et al.  Alanine Amino Transferase Concentrations Are Linked to Folate Intakes and Methylenetetrahydrofolate Reductase Polymorphism in Obese Adolescent Girls , 2006, Journal of pediatric gastroenterology and nutrition.