Fatty acid metabolism: Implications for diet, genetic variation, and disease
Introduction
The epidemic spread of obesity and metabolic syndrome is raising public health concerns across the globe. The factors that distinguish these diseases are also known contributors to cardiovascular disease and cancer, the two most common causes of death in the United States (Hoyert & Xu, 2012). Epidemiologic studies have shown an increased prevalence of these diseases in immigrating populations to Western societies (Nasseri and Moulton, 2011, Seeff and McKenna, 2003). One of the major hypotheses to explain this observation is the abrupt and dramatic change in diet upon emigration, particularly changes in dietary fatty acid consumption. A prevailing body of literature suggests not only the quantity, but more importantly, the quality, of dietary fat consumption modulates disease (Berquin et al., 2011, Berquin et al., 2007, Suburu and Chen, 2012). Specifically, dietary omega-6 polyunsaturated fatty acid (PUFA) can be pro-inflammatory mediators, while omega-3 PUFA acts as anti-inflammatory mediators (Serhan & Petasis, 2011). As such, tipping the balance of an immigrant’s dietary consumption can lead to a chronic state of inflammation and promote the development and progression of cardiovascular disease and cancer.
New evidence suggests various populations may differentially metabolize dietary fatty acids (Teslovich et al., 2010), implying that the risk for chronic inflammation, metabolic syndrome, and cardiovascular disease may be inheritable. Even the progression of cancer, which is well known to be a disease of genetic alterations, can be exacerbated by pro-inflammatory lipid metabolism (Wang & Dubois, 2010). Discrepancies observed in the incidence of cardiovascular disease and cancer in various ethnic populations have been attributed to socioeconomic variance (Marmot, Allen, Bell, Bloomer, & Goldblatt, 2012). However, more recent data suggests genetic diversity in the form of single nucleotide polymorphisms (SNPs) found in several lipid metabolism genes may be a major contributing factor to these epidemiological health disparities (Illig et al., 2010, Kathiresan et al., 2009, Teslovich et al., 2010). Despite the potential inheritance of genetic risk factors for cardiovascular disease and cancer progression, advancements in the new field of metabolomics are yielding promising work to identify metabolic biomarkers of disease that may fuel diagnostic testing and/or predict health outcome. The purpose of this article is to review de novo and dietary fatty acid metabolism and highlight the most recent findings in genetic variation found in fatty acid metabolism genes as they relate to dietary fat consumption and various diseases.
Section snippets
Fatty acids: a biological necessity
Fatty acids are fundamental molecules of cellular biology. Composed of hydrogenated carbons with a carboxyl moiety at the alpha carbon, mammalian fatty acids are divided into three major groups based on the quantity of double bonds found within the carbon chain: saturated fatty acids (SAFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA). SAFA are fully hydrogenated, containing zero double bonds. They are a primary constituent of glycerolipids as well as
Dietary fat metabolism studies – the critical need for standardized methods
An exceptionally large and continuously growing body of literature has investigated the role of dietary fatty acids in disease progression, but conflicting results have lead to disparate conclusions, and for many, an elusive uncertainty of how dietary fatty acids modulate disease. Although the enzymatic pathways of dietary fatty acid metabolism are fairly well understood, new knowledge of the role of dietary fat in disease progression is hindered by several complexities in the design and
Genetic variation modifies fatty acid metabolism
In an era of genomic profiling, whereby genes are well known contributors to disease, our increasing knowledge of the enzymatic pathways in de novo and dietary fatty acid metabolism has fostered research identifying interactions between genetic and dietary modulators of disease. The recent coming of genome-wide association studies (GWAS) has lead to the identification of several new lipid metabolism genes (Teslovich et al., 2010), although it does require extremely laborious and low-throughput
Epigenetic remodeling: diet, exercise, and metabolomic biomarkers
It is now well established that not only genes and the variation found among them, but also the epigenetic modifications, such as methylation, acetylation, and phosphorylation, on the DNA and/or histones can act as modulators of disease. It is known that even RNA, acting as micro-RNA or long, non-coding RNA, can regulate gene expression. Moreover, it is becoming ever clearer that epigenetic modifications can be readily inherited, particularly during the extremely vulnerable in utero stage of
Conclusions and future perspectives
Fatty acids are essential to life. Whether produced de novo or acquired by diet fatty acids play a critical role as constituents of cellular membrane, posttranslational modifications, signaling ligands, and other cellular processes. There many different kinds of fatty acids that each vary in their carbon chain length and degree of saturation, which are important characteristics that help define the biochemical properties and functions of fatty acids. The metabolism of fatty acids has become a
References (123)
- et al.
Genetic adaptation of fatty-acid metabolism: A human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids
American Journal of Human Genetics
(2012) - et al.
Atp-citrate lyase deficiency in the mouse
Journal of Biological Chemistry
(2004) - et al.
Single nucleotide polymorphisms in the fads gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios
Journal of Lipid Research
(2010) - et al.
Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the european prospective investigation on cancer (epic)
European Journal of Cancer
(2011) - et al.
“New” Hepatic fat activates pparalpha to maintain glucose, lipid, and cholesterol homeostasis
Cell Metabolism
(2005) - et al.
Inactivation of hypothalamic fas protects mice from diet-induced obesity and inflammation
Journal of Lipid Research
(2009) - et al.
Personal omics profiling reveals dynamic molecular and medical phenotypes
Cell
(2012) - et al.
Leptin and the control of metabolism: Role for stearoyl-coa desaturase-1 (scd-1)
Journal of Nutrition
(2004) Getting to the root of america’s racial health inequalities
Lancet
(2012)- et al.
Srebp transcription factors: Master regulators of lipid homeostasis
Biochimie
(2004)
Overexpression of fatty acid synthase is associated with palmitoylation of wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer
Laboratory Investigation
Genetic variations at the lipoprotein lipase gene influence plasma lipid concentrations and interact with plasma n-6 polyunsaturated fatty acids to modulate lipid metabolism
Atherosclerosis
Genetic variation in stearoyl-coa desaturase 1 is associated with metabolic syndrome prevalence in costa rican adults
Journal of Nutrition
Regulation of inflammation in cancer by eicosanoids
Prostaglandins and Other Lipid Mediators
The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice
Progress in Lipid Research
Essential role of elovl4 protein in very long chain fatty acid synthesis and retinal function
Journal of Biological Chemistry
Significance of glycosphingolipid fatty acid chain length on membrane microdomain-mediated signal transduction
FEBS Letters
Fads gene polymorphisms in koreans: Association with omega6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease
Atherosclerosis
Do fads genotypes enhance our knowledge about fatty acid related phenotypes?
Clinical Nutrition
Association analyses of single nucleotide polymorphisms in bovine stearoyl-coa desaturase and fatty acid synthase genes with fatty acid composition in commercial cross-bred beef steers
Animal Genetics
Absence of stearoyl-coa desaturase-1 ameliorates features of the metabolic syndrome in ldlr-deficient mice
Journal of Lipid Research
Who european review of social determinants of health and the health divide
Lancet
Polymorphisms in fads1 and fads2 alter desaturase activity in young caucasian and asian adults
Molecular Genetics and Metabolism
Lipoprotein lipase: Genetics, lipid uptake, and regulation
Journal of Lipid Research
Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives. Molecular Aspects of Medicine
Targeted disruption of stearoyl-coa desaturase1 gene in mice causes atrophy of sebaceous and meibomian glands and depletion of wax esters in the eyelid
Journal of Nutrition
Deletion of elovl5 leads to fatty liver through activation of srebp-1c in mice
Journal of Lipid Research
Brca1 affects lipid synthesis through its interaction with acetyl-coa carboxylase
Journal of Biological Chemistry
Acc2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat
Journal of Lipid Research
Fatty acid synthase modulates homeostatic responses to myocardial stress
Journal of Biological Chemistry
Association of acacb polymorphisms with obesity and diabetes
Molecular Genetics and Metabolism
A shift in sphingolipid composition from c24 to c16 increases susceptibility to apoptosis in hela cells
Biochimica et Biophysica Acta
Macrophage fatty-acid synthase deficiency decreases diet-induced atherosclerosis
Journal of Biological Chemistry
Mutant mice lacking acetyl-coa carboxylase 1 are embryonically lethal
Proceedings of the National Academy of Sciences of the United States of America
Experimental models of developmental programming: Consequences of exposure to an energy rich diet during development
Journal of Physiology
Genetic variation in fatty acid elongases is not associated with intermediate cardiovascular phenotypes or myocardial infarction
European Journal of Clinical Nutrition
The midwife, the coincidence, and the hypothesis
British Medical Journal
Effects of a rapeseed oil-enriched hypoenergetic diet with a high content of alpha-linolenic acid on body weight and cardiovascular risk profile in patients with the metabolic syndrome
British Journal of Nutrition
Lexicon of lipid nutrition
Pure and Applied Chemistry Chimie Pure et Appliquée
Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids
Journal of Clinical Investigation
Polyunsaturated fatty acid metabolism in prostate cancer
Cancer and Metastasis Reviews
Role of hepatic desaturases in obesity-related metabolic disorders
Current Opinion in Clinical Nutrition and Metabolic Care
Exercise and gene expression: Physiological regulation of the human genome through physical activity
Journal of Physiology
Nutrition, epigenetics, and developmental plasticity: Implications for understanding human disease
Annual Review of Nutrition
Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and vldl production in mice
Journal of Clinical Investigation
Essential role of elovl4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival
International Journal of Biological Sciences
Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk
Breast Cancer Research and Treatment
Functional desaturase fads1 (delta5) and fads2 (delta6) orthologues evolved before the origin of jawed vertebrates
PLoS One
Cited by (30)
Setting impurity limits for endogenous substances: Recommendations for a harmonized procedure and an example using fatty acids
2022, Regulatory Toxicology and PharmacologyPUFA, genotypes and risk for cardiovascular disease
2022, Prostaglandins Leukotrienes and Essential Fatty AcidsCitation Excerpt :Age-related decrease in the EPA/AA ratio was also reported in overweight subjects with minor alleles of FADS1-rs174547. FADS1/FADS2 genotypes, rs174537, rs174561, and rs3834458 interacts with dietary EPA+DHA to modulate D5D/D6D activity [25-55, 86]. FADS1 and FADS2 cluster has five haplotype blocks with many non-functional SNPs exhibiting varying degree of linkage disequilibrium.
A bioorthogonal chemical reporter for fatty acid synthase–dependent protein acylation
2021, Journal of Biological ChemistryEffects of feeding regimens on meat quality, fatty acid composition and metabolism as related to gene expression in Chinese Sunit sheep
2018, Small Ruminant ResearchCitation Excerpt :This result differs with previous studies (Dervishi et al., 2011; Benítez et al., 2015), but other studies reported that a high concentration of n-3 PUFA inhibited expression of SCD (Waters et al., 2009; Hiller et al., 2011). The enzymes △5 desaturase and △6 desaturase are encoded by the FADS1 and FADS2 genes and have been identified in the biosynthesis of PUFA (Suburu et al., 2013). Elongase5 encoded by the Elove5 genes, are also involved in long chain PUFA biosynthesis (Urrutia et al., 2015).