Carboxylic Acid
Introduction
Section titled “Introduction”Carboxylic acids are a fundamental class of organic compounds characterized by the presence of at least one carboxyl group (-COOH). This functional group consists of a carbonyl (C=O) and a hydroxyl (-OH) group attached to the same carbon atom. They are ubiquitous in nature, serving as essential components and intermediates in virtually all biological systems.
Biological Basis
Section titled “Biological Basis”In biological contexts, carboxylic acids are central to metabolism and cellular structure. They form the backbone of fatty acids, which are critical for energy storage, membrane formation, and signaling pathways. Amino acids, the building blocks of proteins, also contain a carboxyl group. Many key metabolic intermediates, such as pyruvate, lactate, and the components of the Krebs cycle, are carboxylic acids.
Research highlights the significant role of genetic variants in influencing carboxylic acid metabolism. Enzymes like short-chain acyl-Coenzyme A dehydrogenase (SCAD) and medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are crucial for initiating the beta-oxidation of fatty acids, a process that generates energy. Polymorphisms such as intronic SNP rs2014355 in SCAD and rs11161510 in MCAD are associated with the ratios of short-chain and medium-chain acylcarnitines, respectively. These acylcarnitines are indirect substrates, and variations can alter enzymatic turnover..[1] The FADS1 gene cluster also plays a role in the composition of fatty acids in phospholipids and polyunsaturated fatty acids (PUFAs). For instance, the minor allele of rs174548 in FADS1is linked to reduced concentrations of arachidonic acid and specific phosphatidylcholines, which are products ofFADS1 activity..[1]Another important biological carboxylic acid is uric acid, a product of purine metabolism. Its blood concentrations are influenced by genes such asSLC2A9, with notable sex-specific effects..[2] Furthermore, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a key regulator in the mevalonate pathway, which is responsible for cholesterol synthesis. Genetic variations in HMGCR can impact the alternative splicing of exon 13 and affect LDL-cholesterol levels..[3]
Clinical Relevance
Section titled “Clinical Relevance”Disruptions in carboxylic acid metabolism can lead to a range of clinical conditions. Deficiencies in enzymes likeSCAD or MCAD can cause severe systemic disorders, including hypoketotic hypoglycemia, lethargy, encephalopathy, and seizures..[1]While severe forms are often detected through newborn screening, more common genetic variants in these enzymes, even with moderate phenotypic expression, may predispose individuals to impaired beta-oxidation. This can lead to symptoms like tiredness, loss of alertness, headache, and memory problems, particularly during prolonged fasting or intense physical activity, due to increased susceptibility to hypoglycemia..[1] Variations in fatty acid composition, influenced by genes like FADS1, are relevant to cardiovascular health, inflammation, and neurological function..[1]Elevated levels of uric acid are associated with conditions such as gout and kidney stones, making the genetic influences on its concentration, like those fromSLC2A9, important for understanding disease risk..[2] Similarly, genetic factors affecting cholesterol synthesis via HMGCRare critical for understanding and managing dyslipidemia and the risk of coronary artery disease..[3]
Social Importance
Section titled “Social Importance”Understanding the genetic basis of carboxylic acid metabolism is vital for advancing personalized medicine and public health. The identification of genetic variants that alter the homeostasis of key metabolites provides crucial insights into the molecular mechanisms underlying complex diseases. This knowledge can inform tailored dietary recommendations, targeted therapeutic interventions, and the development of new strategies for preventing and managing metabolic disorders, ultimately contributing to improved individual and population health outcomes..[1]
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The comprehensive understanding of genetic influences on a trait is often constrained by the inherent limitations of study design and statistical power. Genome-wide association studies (GWAS) typically utilize a subset of all available single nucleotide polymorphisms (SNPs), relying on imputation from reference panels. This partial coverage of genetic variation means that some causal variants or entire genes influencing the trait might not be directly assayed or accurately imputed, thereby limiting the ability to comprehensively characterize genetic contributions . A reduced catalytic activity or protein abundance of FADS1 due to a genetic polymorphism can lead to an imbalance, resulting in increased levels of eicosatrienoyl-CoA (C20:3) and decreased levels of arachidonyl-CoA (C20:4), which are direct substrate and product of the delta-5 desaturase reaction, respectively.[1]This alteration directly impacts the availability of long-chain PUFAs, such as arachidonic acid, influencing their incorporation into glycerophospholipids and other lipid classes, thereby modifying overall carboxylic acid profiles.
Two other important genes involved in fatty acid metabolism are SCAD (short-chain acyl-Coenzyme A dehydrogenase) and MCAD (medium-chain acyl-Coenzyme A dehydrogenase). Both enzymes are critical for initiating the beta-oxidation of fatty acids, a process that breaks down carboxylic acids for energy.[1]An intronic single nucleotide polymorphism (SNP),rs2014355 , in the SCAD gene is significantly associated with the ratio of short-chain acylcarnitines C3 and C4.[1] Similarly, rs11161510 , an intronic SNP in the MCAD gene, shows a strong association with the ratio of medium-chain acylcarnitines.[1]These acylcarnitines are carboxylic acid derivatives that play a vital role in transporting fatty acids for beta-oxidation, and variations in these genes can thus impact the efficiency of fatty acid metabolism and energy production.
Beyond fatty acids, genetic variants also influence the metabolism of other carboxylic acids like uric acid. TheSLC2A9gene encodes a facilitative glucose transporter protein that functions as a crucial urate transporter, significantly influencing serum uric acid concentrations and excretion.[2] Polymorphisms in SLC2A9have pronounced, often sex-specific, effects on uric acid levels and are associated with conditions like gout.[2] Additionally, the GCKR(glucokinase regulator) gene, which plays a role in glucose and lipid metabolism, contains the variantrs780094 , which has been associated with serum urate levels.[4]These genetic associations highlight how variations in transporter and metabolic regulatory genes can profoundly affect the body’s handling of uric acid, a key carboxylic acid involved in purine metabolism.
Definition and Structural Nomenclature
Section titled “Definition and Structural Nomenclature”Fatty acids, a fundamental class of carboxylic acids, are organic compounds characterized by a carboxyl group attached to a long aliphatic chain. In the context of lipid side chains, their composition is precisely abbreviated as Cx:y, where ‘x’ signifies the total number of carbon atoms within the side chain and ‘y’ denotes the number of double bonds present.[1] This standardized nomenclature allows for clear communication regarding their molecular structure, although specific positional isomers or stereochemical differences may not always be discernible through certain analytical methods.[1] This molecular definition is crucial for understanding their diverse roles in biological systems.
Classification and Metabolic Subtypes
Section titled “Classification and Metabolic Subtypes”Fatty acids are broadly classified based on their chain length and degree of saturation, impacting their metabolic processing. For instance, short-chain and medium-chain fatty acids are distinct subtypes, each preferentially metabolized by specific enzymes such as short-chain acyl-Coenzyme A dehydrogenase (SCAD) and medium-chain acyl-Coenzyme A dehydrogenase (MCAD), respectively.[1] These dehydrogenases initiate the beta-oxidation process, highlighting a functional classification based on their enzymatic pathways.[1] Additionally, the classification extends to polyunsaturated fatty acids, whose composition in phospholipids is influenced by gene clusters like FADS1 and FADS2, indicating another important biological subtype.[5]
Measurement and Clinical Relevance
Section titled “Measurement and Clinical Relevance”The concentrations and ratios of specific fatty acid metabolites serve as critical diagnostic and measurement criteria, reflecting underlying metabolic states. Fatty acids are bound to free carnitine for transport and beta-oxidation into the mitochondria, forming acylcarnitines.[1] Therefore, the ratios of short-chain acylcarnitines like C3 and C4, or specific medium-chain acylcarnitines, are operational definitions used as indirect substrates for assessing the activity of enzymes such as SCAD and MCAD, respectively.[1] Elevated concentrations of longer-chain fatty acids relative to their smaller-chain products can imply reduced dehydrogenase activity, providing insight into metabolic dysfunction and potential genetic predispositions, such as those associated with rs2014355 in SCAD or rs11161510 in MCAD.[1] These measurements are vital for understanding genetically determined metabotypes and their influence on common multi-factorial diseases.[1]
Biological Background of Carboxylic Acids
Section titled “Biological Background of Carboxylic Acids”Carboxylic acids are organic compounds characterized by a carboxyl group (-COOH) and are indispensable to life, playing diverse roles from fundamental energy metabolism to complex signaling pathways and genetic regulation. In biological systems, they encompass a broad range of molecules, including fatty acids, amino acids, and various metabolic intermediates, each contributing uniquely to cellular and systemic functions. Their chemical properties, particularly their acidity and ability to form esters, enable them to participate in a multitude of biochemical reactions that are central to maintaining homeostasis and responding to physiological challenges.
Metabolic Centrality of Carboxylic Acids
Section titled “Metabolic Centrality of Carboxylic Acids”Carboxylic acids, particularly fatty acids, are fundamental to numerous biological processes, serving as critical energy sources and building blocks for complex lipids. Fatty acids undergo beta-oxidation within the mitochondria, a catabolic process initiated by enzymes like short-chain acyl-Coenzyme A dehydrogenase (SCAD) and medium-chain acyl-Coenzyme A dehydrogenase (MCAD), which differ in their substrate chain length preference.[1]To facilitate this crucial mitochondrial transport, fatty acids are first bound to free carnitine, forming acylcarnitines, which are key intermediates in this metabolic pathway.[1] Beyond energy generation, carboxylic acids are integral to the synthesis of essential biomolecules, including long-chain polyunsaturated fatty acids derived from essential linoleic (C18:2) and alpha-linolenic (C18:3) acids through omega-6 and omega-3 synthesis pathways, respectively.[1] Additionally, saturated and monounsaturated fatty acids such as palmitic (C16:0), stearic (C18:0), and oleic (C18:1) acids can be synthesized de novo, highlighting their versatile roles in maintaining cellular structure and function.[1]These fatty acid moieties are then incorporated into glycerophospholipids, like phosphatidylcholines (PC), via pathways such as the Kennedy pathway, where they are linked to glycerol 3-phosphate to form vital membrane components.[1], [6] For instance, the delta-5 desaturase enzyme, encoded by FADS1, is crucial for converting eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4), which are then utilized in the synthesis of specific glycerophospholipids like PC aa C36:3 and PC aa C36:4.[1] Furthermore, the mevalonate pathway, regulated by 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), relies on short-chain carboxylic acid derivatives for cholesterol biosynthesis, demonstrating the broad involvement of these compounds in metabolic regulatory networks.[7]Another significant enzyme, carboxypeptidase N, an amino acid-cleaving enzyme found in human plasma, regulates inflammation and processes peptides, underscoring the diverse roles of carboxylic acid-containing molecules in systemic physiology.[8], [9]
Genetic Influences on Carboxylic Acid Metabolism
Section titled “Genetic Influences on Carboxylic Acid Metabolism”Genetic variations significantly impact the efficiency and regulation of carboxylic acid metabolism, influencing the concentrations of various metabolites and their derivatives. Polymorphisms within genes encoding metabolic enzymes, such asFADS1 (fatty acid desaturase 1), can reduce the catalytic activity of delta-5 desaturase, leading to altered levels of its substrates and products, like eicosatrienoyl-CoA (C20:3) and arachidonyl-CoA (C20:4), and subsequently affecting the composition of phospholipids.[1], [5], [10] Specifically, a reduced FADS1 activity might result in increased concentrations of PC aa C36:3 and decreased concentrations of PC aa C36:4, demonstrating how genetic variants can directly modify lipid profiles.[1]Similarly, intronic single nucleotide polymorphisms (SNPs) likers2014355 in SCAD and rs11161510 in MCAD are strongly associated with the ratios of short-chain and medium-chain acylcarnitines, respectively, indicating their influence on fatty acid beta-oxidation efficiency.[1] These genetic associations reveal that individuals homozygous for certain minor alleles in SCAD and MCAD may exhibit lower enzymatic turnover for their respective reactions, impacting the body’s ability to process fatty acids.[1] Beyond fatty acid metabolism, common SNPs in HMGCR(3-hydroxy-3-methylglutaryl coenzyme A reductase) are linked to low-density lipoprotein (LDL) cholesterol levels, with specific variants affecting the alternative splicing of exon 13, thus modulating the enzyme’s function and overall cholesterol synthesis.[3] Furthermore, the gene SLC2A9is recognized for its role in influencing uric acid concentrations, with pronounced sex-specific effects, and is identified as a transporter impacting serum urate levels and excretion, thereby influencing conditions like gout.[2], [11] These examples collectively highlight how specific genetic loci act as critical regulatory elements, shaping individual metabolic profiles and susceptibility to various physiological states.
Pathophysiological Roles and Systemic Consequences
Section titled “Pathophysiological Roles and Systemic Consequences”Disruptions in carboxylic acid metabolism are implicated in a range of pathophysiological processes, affecting tissue and organ-level biology and contributing to systemic health outcomes. For instance, genetic variations that impair the function of enzymes likeSCAD and MCAD can lead to reduced beta-oxidation activity, potentially resulting in the accumulation of specific acylcarnitines, which are markers for metabolic disorders.[1] The routine newborn screening for medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency), for example, underscores the clinical significance of these genetic predispositions and their impact on metabolic health from early development.[12]Moreover, the enzyme carboxypeptidase N, which processes peptides containing C-terminal basic amino acids, acts as a pleiotropic regulator of inflammation, indicating a broader role for carboxylic acid-related enzymes in immune responses and homeostatic balance.[9], [13]The systemic consequences of altered carboxylic acid metabolism extend to major health concerns such as cardiovascular disease and metabolic syndrome. Variations inHMGCR, a key enzyme in cholesterol synthesis, are associated with LDL-cholesterol levels, directly linking genetic factors in carboxylic acid pathways to lipid homeostasis and the risk of coronary artery disease.[3], [14] Similarly, the SLC2A9gene’s influence on uric acid concentrations directly impacts serum urate levels, excretion, and the susceptibility to gout, highlighting how a single gene affecting a carboxylic acid metabolite can have significant systemic effects.[2], [11]Beyond specific diseases, genetic variations in fatty acid metabolism have even been linked to neurodevelopmental outcomes, such as the moderation of breastfeeding effects on IQ, suggesting a critical role for these biomolecules in brain development and function.[15] The relevance of these metabolites is also observed in conditions like diabetes, where metabolomics analysis can uncover important metabolic insights.[16]
Carboxylic Acids as Markers of Physiological State and Disease Susceptibility
Section titled “Carboxylic Acids as Markers of Physiological State and Disease Susceptibility”The comprehensive measurement of endogenous metabolites, including various carboxylic acids and their derivatives, serves as a functional readout of the physiological state of the human body, providing insights into health and disease.[1]Metabolomics studies, which quantify compounds like free carnitine, acylcarnitines, prostaglandins, and diverse phospholipids, demonstrate that the concentrations of these molecules, and particularly their ratios, can strongly indicate the efficiency of specific metabolic reactions.[1] For example, the ratio between product-substrate pairs of the delta-5 desaturase reaction, such as [PC aa C36:4]/[PC aa C36:3], provides a robust indicator for the catalytic efficiency of FADS1.[1] Such genetically determined “metabotypes,” which reflect variations in key lipids, carbohydrates, or amino acids, are recognized as significant cofactors in the etiology of common multifactorial diseases.[1]These metabotypes, often influenced by frequent genetic polymorphisms, interact with environmental factors like nutrition and lifestyle to modulate an individual’s susceptibility to various phenotypes.[1]Genome-wide association studies (GWAS) have successfully identified genetic variants that directly impact metabolite conversion and modification, offering access to the underlying molecular mechanisms of disease.[1] The strong associations observed between specific gene variants (e.g., in SCAD or MCAD) and acylcarnitine ratios underscore how genetic predispositions translate into distinct metabolic profiles, which can be critical for understanding disease pathogenesis and developing targeted interventions.[1] Thus, carboxylic acids and their metabolic pathways not only reflect the current physiological state but also serve as crucial indicators of genetic susceptibility to a wide array of health conditions.
Metabolic Processing of Carboxylic Acids
Section titled “Metabolic Processing of Carboxylic Acids”Carboxylic acids, particularly fatty acids, undergo intricate metabolic processing crucial for energy production and biosynthesis. Long-chain fatty acids are transported into mitochondria by binding to free carnitine, where they initiate beta-oxidation.[1] This catabolic process is catalyzed by specific acyl-Coenzyme A dehydrogenases, such as short-chain acyl-Coenzyme A dehydrogenase (SCAD) and medium-chain acyl-Coenzyme A dehydrogenase (MCAD), which differ in their substrate chain length preferences.[1] The efficiency of these enzymatic reactions dictates the flux of fatty acid breakdown, impacting the availability of energy and metabolic intermediates.[1] Beyond catabolism, the biosynthesis and modification of carboxylic acids are also tightly regulated. The fatty acid delta-5 desaturase (FADS1) enzyme plays a key role in modifying fatty acid composition, affecting levels of crucial polyunsaturated fatty acids like arachidonic acid.[1]This desaturation process is vital for producing specific lipids required for membrane structure and signaling molecules. Another significant pathway involving carboxylic acid derivatives is the mevalonate pathway, which is responsible for cholesterol biosynthesis and other isoprenoids, highlighting the broad involvement of these compounds in cellular anabolism.[7]
Genetic and Regulatory Control of Carboxylic Acid Homeostasis
Section titled “Genetic and Regulatory Control of Carboxylic Acid Homeostasis”The regulation of carboxylic acid levels is profoundly influenced by genetic factors and molecular control mechanisms. Genetic variants, such as intronic SNPs likers2014355 in SCAD and rs11161510 in MCAD, can significantly alter enzymatic turnover, leading to modified concentrations of their respective substrates and products, such as acylcarnitines.[1] Specifically, minor allele homozygotes for these SNPs have been shown to exhibit lower enzymatic activity, resulting in higher concentrations of longer-chain fatty acids (substrates) compared to shorter-chain products.[1] This genetic influence extends to the FADS gene cluster, where common variants in FADS1 and FADS2 are associated with the fatty acid composition in phospholipids and polyunsaturated fatty acids.[5], [10] Regulatory mechanisms also encompass post-translational modifications and gene expression control. For instance, common SNPs in HMGCR, a key enzyme in the mevalonate pathway, can affect the alternative splicing of exon13, thereby influencing LDL-cholesterol levels.[3] This demonstrates how genetic variations can impact protein function and, consequently, metabolic pathways at a fundamental level. Analyzing ratios of metabolite concentrations, particularly direct substrates and products of enzymatic reactions, serves as a powerful method to infer the efficiency of enzymatic conversions and understand metabolic regulation.[1]
Carboxylic Acids in Interconnected Pathways and Systemic Integration
Section titled “Carboxylic Acids in Interconnected Pathways and Systemic Integration”Carboxylic acids are integral to a vast network of interconnected metabolic pathways, contributing to systemic integration and overall physiological function. Metabolomics, the comprehensive measurement of endogenous metabolites, provides a functional readout of the human body’s physiological state, revealing how genetic variants affect the homeostasis of key lipids, carbohydrates, and amino acids.[1] This approach highlights pathway crosstalk, where changes in one pathway, such as fatty acid metabolism, can ripple through others, influencing overall lipid profiles and energy balance.[1]Uric acid, a carboxylic acid, exemplifies specific transport and regulatory mechanisms within the body. TheSLC2A9 gene, also known as GLUT9, encodes a urate transporter that significantly influences serum uric acid concentrations and its excretion.[2], [17] Alternative splicing of SLC2A9can alter its trafficking, affecting the efficiency of urate transport.[18] This demonstrates how specific carboxylic acids are not merely metabolic intermediates but are actively regulated through dedicated transport systems that integrate with broader physiological processes, including renal function.[19]
Dysregulation and Disease Implications
Section titled “Dysregulation and Disease Implications”Dysregulation in carboxylic acid pathways is frequently implicated in the etiology of various diseases, offering insights into potential therapeutic targets. Genetically determined metabotypes, or metabolic profiles, are recognized as discriminating cofactors in common multi-factorial diseases, influencing individual susceptibility in interaction with environmental factors.[1] For example, specific genotypes of ACADM, the gene for medium-chain acyl-CoA dehydrogenase, are correlated with biochemical phenotypes observed in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency, a significant metabolic disorder.[12]Furthermore, associations between fatty acid desaturase genes and conditions like attention-deficit/hyperactivity disorder underscore the broad impact of carboxylic acid metabolism on health.[20]Elevated uric acid levels, resulting from dysregulation of its transport or metabolism, are linked to the metabolic syndrome and renal disease.[21]Genetic variants that affect lipid concentrations, including carboxylic acids, are also associated with the risk of cardiovascular diseases and dyslipidemia, highlighting the critical role of these pathways in maintaining cardiovascular health.[4], [14], [22] Understanding these dysregulations through approaches like metabolomics is vital for diagnosing metabolic diseases and identifying novel biomarkers.[23]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs37369 rs40199 | AGXT2 | serum dimethylarginine amount metabolite measurement urinary metabolite measurement protein measurement X-12117 measurement |
References
Section titled “References”[1] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, vol. 4, no. 11, 2008, e1000282.
[2] Doring, A. et al. “SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.”Nat Genet, vol. 40, no. 4, 2008, pp. 430–436.
[3] Burkhardt R, et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, 2008.
[4] Wallace C, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, 2008, pp. 139–149.
[5] Schaeffer L, et al. “Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.” Hum Mol Genet, vol. 15, 2006, pp. 1745–1756.
[6] Vance, J. E. “Membrane Lipid Biosynthesis.” Encyclopedia of Life Sciences, John Wiley & Sons, Ltd, 2001.
[7] Goldstein JL, Brown MS. “Regulation of the mevalonate pathway.” Nature, vol. 343, 1990, pp. 425–430.
[8] Skidgel, R. A., et al. “Amino Acid Sequence of the N-Terminus and Selected Tryptic Peptides of the Active Subunit of Human Plasma Carboxypeptidase N: Comparison with Other Carboxypeptidases.”Biochem. Biophys. Res. Commun., vol. 154, no. 3, 1988, pp. 1323–1329.
[9] Matthews, K. W., et al. “Carboxypeptidase N: A Pleiotropic Regulator of Inflammation.” Mol. Immunol., vol. 40, no. 11, 2004, pp. 785–793.
[10] Malerba G, et al. “SNPs of the FADS Gene Cluster are Associated with Polyunsaturated Fatty Acids in a Cohort of Patients with Cardiovascular Disease.”Lipids, vol. 43, 2008, pp. 289–299.
[11] Vitart, V., et al. “SLC2A9Is a Newly Identified Urate Transporter Influencing Serum Urate Concentration, Urate Excretion and Gout.”Nat Genet, vol. 40, no. 4, 2008, pp. 437–442.
[12] Maier EM, et al. “Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency.” Hum Mutat, vol. 25, 2005, pp. 443–452.
[13] Yuan, X., et al. “Population-Based Genome-Wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes.” Am J Hum Genet, vol. 83, no. 4, 2008, pp. 520–528.
[14] Willer CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, 2008.
[15] Caspi, A., et al. “Moderation of Breastfeeding Effects on the IQ by Genetic Variation in Fatty Acid Metabolism.” Proc Natl Acad Sci U S A, vol. 104, no. 47, 2007, pp. 18860–18865.
[16] Altmaier, E. et al. “Bioinformatics analysis of targeted metabolomics - uncovering old and new tales of diabetic mice under medication.” Endocrinology, vol. 149, 2008, pp. 3478–3489.
[17] Vitart V, et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.”Nat Genet, 2007.
[18] Augustin R, et al. “Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.”J Biol Chem, vol. 279, no. 16, 2004, pp. 16229–36.
[19] Anzai N, et al. “New insights into renal transport of urate.”Curr Opin Rheumatol, vol. 19, no. 2, 2007, pp. 151–7.
[20] Brookes KJ, et al. “Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder.” Biol Psychiatry, vol. 60, 2006, pp. 1053–1061.
[21] Cirillo P, et al. “Uric Acid, the metabolic syndrome, and renal disease.”J Am Soc Nephrol, vol. 17, no. 12 Suppl 3, 2006, pp. S165–S168.
[22] Kathiresan S, et al. “Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.”Nat Genet, 2008.
[23] Weinberger KM. “Metabolomics in diagnosing metabolic diseases.” Ther Umsch, vol. 65, 2008, pp. 487–491.