Decenoylcarnitine
Introduction
Section titled “Introduction”Decenoylcarnitine is an acylcarnitine, a class of organic compounds formed when a fatty acid is chemically bonded to carnitine. These molecules are essential for cellular energy production, playing a critical role in the transport of fatty acids across the mitochondrial membrane for subsequent beta-oxidation.[1]Decenoylcarnitine specifically refers to an acylcarnitine containing a 10-carbon fatty acid chain, placing it in the category of medium-chain acylcarnitines. Its presence and concentration in biological fluids are key indicators of metabolic health and the efficiency of fatty acid processing within the body.
Biological Basis
Section titled “Biological Basis”The primary biological function of decenoylcarnitine is its involvement in mitochondrial fatty acid beta-oxidation. Fatty acids, once activated to acyl-CoAs, are converted into acylcarnitines to facilitate their entry into the mitochondria. Inside the mitochondria, these acylcarnitines are converted back to acyl-CoAs, becoming substrates for a series of enzymes that progressively shorten the fatty acid chain, releasing energy. For medium-chain fatty acids, enzymes such as medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are crucial for initiating this breakdown. [1]Consequently, decenoylcarnitine levels reflect the activity of these metabolic pathways, and imbalances can indicate disruptions in fatty acid metabolism. Genetic variations affecting the function of enzymes likeMCAD can alter the profile of acylcarnitines, impacting how the body processes fats. [1]
Clinical Relevance
Section titled “Clinical Relevance”Variations in decenoylcarnitine concentrations have significant clinical relevance, particularly in the context of inherited metabolic disorders. Elevated levels of decenoylcarnitine and other medium-chain acylcarnitines can be a diagnostic marker for conditions such asMCAD deficiency, a genetic disorder that impairs the body’s ability to metabolize medium-chain fatty acids. Early detection through metabolomic screening, which measures a wide array of metabolites in bodily fluids, is crucial for timely intervention and management of such conditions. [1] Research, including genome-wide association studies (GWAS), has identified specific genetic variants, such as the intronic SNP rs11161510 in the MCAD gene, that are strongly associated with altered levels of medium-chain acylcarnitines. [1] These findings suggest that genetic predispositions can profoundly influence an individual’s metabolic profile and susceptibility to certain health issues. [1]
Social Importance
Section titled “Social Importance”The study and understanding of decenoylcarnitine and its genetic determinants carry considerable social importance. Comprehensive metabolomic and genomic analyses contribute to the development of personalized medicine, allowing for tailored nutritional guidance and therapeutic strategies based on an individual’s unique metabolic and genetic makeup.[1]Early identification of genetic variations that affect fatty acid metabolism can enable proactive health management and potentially mitigate the impact of metabolic disorders. Furthermore, by elucidating how “genetically determined metabotypes” interact with environmental factors like diet and lifestyle, research helps in understanding the complex etiology of common multifactorial diseases.[1]This knowledge empowers individuals and healthcare systems to make more informed decisions regarding disease prevention, risk assessment, and overall health promotion.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The interpretability of genetic associations with decenoylcarnitine levels is subject to several methodological and statistical considerations inherent in large-scale genomic studies. Many investigations employed fixed-effects meta-analysis, which assumes homogeneity across studies and might not fully account for unmeasured variations or true heterogeneity in genetic effects across diverse cohorts.[2] Furthermore, the reliance on imputation based on reference panels like HapMap introduces a degree of uncertainty, with reported error rates for imputed genotypes, potentially affecting the accuracy of identified associations, particularly for less common variants or those not well-represented in the reference panels. [2] The initial genome-wide association screens often utilized study-specific genotyping quality control and analytical criteria, which could lead to inconsistencies across different contributing studies and impact the comparability of findings. [2]
A significant challenge lies in the consistent replication of findings, which is considered the gold standard for validating genetic associations. [1] Studies frequently highlight that a substantial proportion of initial associations fail to replicate in independent cohorts, suggesting a potential for false positive findings or context-specific genetic effects. [3] This issue is compounded by challenges in sorting and prioritizing associated genetic variants for follow-up, especially when findings lack external validation. [3] Additionally, moderate sample sizes in some cohorts can lead to inadequate statistical power, increasing the risk of false negative findings where true, but modest, genetic effects are missed, or conversely, effect sizes might be inflated in initial discovery phases. [3]The assumption of an additive model of inheritance in many analyses might also oversimplify complex genetic architectures, potentially overlooking non-additive effects that could influence decenoylcarnitine levels.[4]
Generalizability and Phenotype Definition
Section titled “Generalizability and Phenotype Definition”The generalizability of findings concerning genetic influences on decenoylcarnitine levels is a notable limitation, primarily due to the demographic characteristics of the study populations. A predominant number of discovery and replication cohorts consisted primarily of individuals of self-reported European ancestry, limiting the direct applicability of these results to other ethnic or racial groups.[4]This lack of ethnic diversity means that genetic variants influencing decenoylcarnitine might operate differently or have varying frequencies in non-European populations, potentially leading to different association patterns or effect sizes. Moreover, some cohorts were largely composed of middle-aged to elderly individuals, introducing a potential age bias and survival bias, as DNA collection often occurred at later examinations, raising questions about the generalizability of findings to younger populations or individuals with different health statuses.[3]
Phenotype definition and measurement also present challenges. While targeted quantitative metabolomics platforms provide precise measurements of acylcarnitines like decenoylcarnitine[1] the handling of confounding factors, such as medication use, varied across studies. For instance, some studies consistently excluded individuals on lipid-lowering therapies, while others imputed untreated values or lacked information on such treatments, creating inconsistencies in phenotype adjustment. [4] These variations in defining the “unperturbed” metabolite level can introduce heterogeneity and complicate direct comparisons across different cohorts. Furthermore, the extensive number of metabolites measured in some studies, while comprehensive, necessitates stringent multiple testing corrections, which could obscure true associations with smaller effect sizes if not appropriately addressed. [1]
Complex Genetic and Environmental Interactions
Section titled “Complex Genetic and Environmental Interactions”Current studies on decenoylcarnitine levels, like many complex traits, face limitations in fully elucidating the intricate interplay between genetic predisposition and environmental factors. Many analyses have not comprehensively investigated gene-environment interactions, despite evidence suggesting that genetic variants can influence phenotypes in a context-specific manner, modulated by environmental influences such as diet or lifestyle.[5]This represents a significant knowledge gap, as understanding these interactions is crucial for a complete picture of decenoylcarnitine regulation and for developing personalized interventions. The observed genetic associations typically explain only a fraction of the total phenotypic variation, implying substantial “missing heritability” that could be attributed to unmeasured environmental factors, rarer genetic variants, or complex epistatic interactions not captured by current GWAS designs.[5]
The influence of unmeasured environmental confounders or lifestyle factors on decenoylcarnitine levels, and their potential interaction with genetic variants, remains largely unexplored. Factors such as dietary intake, physical activity, or other metabolic stressors could significantly modify genetic effects, yet these are often not systematically assessed or integrated into analyses. Consequently, the reported genetic associations, while statistically significant, might represent only a partial view of the biological mechanisms governing decenoylcarnitine concentrations. Further research is needed to move beyond associations to functional validation and to explore these complex gene-environment dynamics to fully understand the biological pathways and clinical implications of altered decenoylcarnitine levels.[3]
Variants
Section titled “Variants”The genetic landscape influencing metabolic pathways, particularly those involving fatty acid oxidation and transport, includes several key genes and their variants that can impact circulating levels of acylcarnitines like decenoylcarnitine. These genetic variations can alter enzyme efficiency or transporter function, leading to measurable differences in metabolic profiles and potentially affecting overall metabolic health. Understanding these variants helps to elucidate the underlying genetic architecture of diverse metabolic traits.
The ACADM gene, encoding Acyl-CoA Dehydrogenase Medium Chain, plays a central role in the mitochondrial beta-oxidation of medium-chain fatty acids, a critical process for energy production. This enzyme breaks down medium-chain acyl-CoAs into shorter derivatives, a fundamental step in energy metabolism. Variants in ACADM, such as rs9410 , can influence the activity of this enzyme, thereby affecting the concentrations of medium-chain acylcarnitines, including decenoylcarnitine (C10:1 acylcarnitine), which is a direct product of medium-chain fatty acid breakdown. Research has strongly associated polymorphisms inMCAD (the gene coding for medium-chain acyl-Coenzyme A dehydrogenase) with the ratio of medium-chain acylcarnitines, highlighting its significant impact on this metabolic pathway. [1] Alterations in ACADM function due to genetic variations can lead to an accumulation of these acylcarnitines, serving as indicators of impaired fatty acid metabolism and potentially contributing to metabolic disturbances. [1]
The ETFDH gene encodes Electron Transfer Flavoprotein Dehydrogenase, an essential enzyme that facilitates the transfer of electrons from various mitochondrial dehydrogenases, including those involved in fatty acid beta-oxidation, to the electron transport chain. This process is crucial for the complete oxidation of fatty acids and efficient energy generation within mitochondria. Genetic variants like rs17843966 and rs7679753 in ETFDHcould affect the efficiency of this electron transfer, potentially hindering overall fatty acid oxidation. Such impairments may result in the buildup of various acylcarnitines, including decenoylcarnitine, as the metabolic flux through the beta-oxidation pathway is compromised.[2] Dysfunctional ETFDHhas been linked to metabolic disorders characterized by defects in both fatty acid and amino acid catabolism, underscoring the broad implications of its genetic variations on systemic metabolism and energy balance.[1]
SLC44A5 is a member of the solute carrier family 44, primarily functioning as a choline transporter-like protein involved in the cellular uptake of choline. Choline is an indispensable nutrient vital for numerous physiological processes, including the structural integrity of cell membranes, the synthesis of neurotransmitters, and lipid metabolism. While direct associations between SLC44A5and decenoylcarnitine are not extensively documented, its role in choline transport can indirectly influence lipid metabolism and broader cellular functions that are intricately connected with fatty acid oxidation pathways.[6] Genetic variations such as rs7552404 could modify the efficiency of choline transport, potentially impacting phospholipid synthesis or the availability of precursors for other metabolic pathways, thereby contributing to broader metabolic phenotypes that might indirectly affect acylcarnitine profiles. [7]
The ABCC1gene codes for an ATP-binding cassette transporter, a protein family recognized for its active transport of a diverse array of substrates, including xenobiotics, drugs, and endogenous metabolites, out of cells.ABCC1 plays a significant role in cellular detoxification and the regulation of intracellular metabolite concentrations, particularly through the efflux of glutathione conjugates and other organic anions. Variants like rs924138 and rs1967120 could influence the transport efficiency of ABCC1, potentially affecting the cellular clearance of metabolic byproducts or the distribution of fatty acid derivatives. [1] Although not directly involved in fatty acid beta-oxidation, altered ABCC1function due to these genetic variations might indirectly affect the cellular environment and metabolic flux, which could, in turn, influence the levels or cellular handling of acylcarnitines such as decenoylcarnitine.[8]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs7552404 | SLC44A5 - ACADM | X-18921 measurement caprylate 8:0 measurement serum metabolite level carnitine measurement octanoylcarnitine measurement |
| rs9410 | PPID | decenoylcarnitine measurement hexanoylcarnitine measurement dodecanoylcarnitine measurement cerebrospinal fluid composition attribute, glutarylcarnitine (C5-DC) measurement |
| rs924138 rs1967120 | ABCC1 | metabolite measurement laurylcarnitine measurement succinylcarnitine measurement X-13431 measurement Cis-4-decenoyl carnitine measurement |
| rs17843966 rs7679753 | ETFDH | blood protein amount protein measurement octanoylcarnitine measurement decanoylcarnitine measurement dodecanoylcarnitine measurement |
Biological Background of Decenoylcarnitine
Section titled “Biological Background of Decenoylcarnitine”Decenoylcarnitine is a specific type of acylcarnitine, which are critical metabolites involved in the transport and metabolism of fatty acids within the body. Understanding its biological role requires examining the intricate molecular pathways of lipid metabolism, the genetic factors that regulate these processes, and their broader implications for systemic health.
Decenoylcarnitine in Mitochondrial Fatty Acid Oxidation
Section titled “Decenoylcarnitine in Mitochondrial Fatty Acid Oxidation”Decenoylcarnitine, a medium-chain acylcarnitine, plays a central role in the energy metabolism of cells, specifically within the process of mitochondrial fatty acid beta-oxidation. Fatty acids, sourced from the diet or synthesized endogenously, must be transported into the mitochondria for their breakdown to generate energy.[1]This transport mechanism relies on free carnitine, which reversibly binds to fatty acids to form acylcarnitines, facilitating their entry across the mitochondrial membrane.[1] Once inside the mitochondria, acylcarnitines release their fatty acid components, which then undergo a series of enzymatic steps in beta-oxidation, initiated by specific acyl-Coenzyme A dehydrogenases, to produce acetyl-CoA for the citric acid cycle. [1]
The concentration of specific acylcarnitines, such as decenoylcarnitine, in bodily fluids like serum provides a functional readout of the physiological state, particularly concerning lipid homeostasis.[1]These metabolites are considered indirect substrates for the enzymes involved in fatty acid oxidation. For instance, medium-chain acylcarnitines like decenoylcarnitine are indirect substrates of theMCAD enzyme, which catalyzes the initial step of beta-oxidation for medium-chain fatty acids. [1]The balance between free carnitine and various acylcarnitines reflects the efficiency and capacity of the fatty acid oxidation pathway, highlighting its importance in cellular energy production and overall metabolic health.[1]
Genetic Regulation of Acylcarnitine Metabolism
Section titled “Genetic Regulation of Acylcarnitine Metabolism”The levels of decenoylcarnitine and other acylcarnitines are significantly influenced by genetic variations, particularly in genes encoding enzymes crucial for fatty acid beta-oxidation. Polymorphisms within the gene coding for medium-chain acyl-Coenzyme A dehydrogenase (MCAD), such as the intronic SNP rs11161510 , are strongly associated with the ratio of medium-chain acylcarnitines. [1] Specifically, minor allele homozygotes for rs11161510 exhibit higher concentrations of longer-chain fatty acids (substrates) compared to smaller-chain fatty acids (products), implying a reduced enzymatic turnover for MCAD. [1] Similarly, variants in the short-chain acyl-Coenzyme A dehydrogenase (SCAD) gene, like the intronic SNP rs2014355 , impact the ratio of short-chain acylcarnitines, indicating similar effects on SCAD activity. [1]
These genetic mechanisms underscore how specific gene functions and regulatory elements can modulate the efficiency of metabolic reactions. The genetic architecture of acylcarnitine metabolism, including variations in MCAD genotypes, has been correlated with biochemical phenotypes observed in newborn screening programs for conditions like medium-chain acyl-CoA dehydrogenase deficiency. [9] Such genetic variants lead to distinct “metabotypes,” which are unique metabolic profiles that reflect an individual’s genetic predisposition and influence their metabolic responses to various physiological demands and environmental factors. [1]
Metabolite Homeostasis and Systemic Health
Section titled “Metabolite Homeostasis and Systemic Health”Disruptions in the homeostatic balance of metabolites, including acylcarnitines like decenoylcarnitine, are intimately linked to broader pathophysiological processes and systemic health. Genetically determined metabotypes, characterized by specific patterns of metabolite concentrations, are recognized as significant cofactors in the etiology of common multi-factorial diseases.[1]These metabotypes can interact with environmental factors, such as nutrition and lifestyle, to influence an individual’s susceptibility to various phenotypes, including those related to lipid concentrations and risk of coronary artery disease.[1]
The comprehensive measurement of endogenous metabolites through metabolomics offers a functional readout of the human body’s physiological state, providing insights into these complex interactions. [1]By understanding how genetic variants alter the homeostasis of key lipids and other metabolites, researchers can better elucidate disease mechanisms and identify potential targets for intervention. The presence and ratios of acylcarnitines in serum, therefore, serve as crucial biomarkers reflecting the efficiency of fatty acid oxidation pathways and their systemic consequences on metabolic health.[1]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Carnitine-Mediated Fatty Acid Catabolism
Section titled “Carnitine-Mediated Fatty Acid Catabolism”Fatty acids are essential energy sources that require specialized transport mechanisms to enter the mitochondria for catabolism. This process initiates with the binding of fatty acids to free carnitine, forming acylcarnitines, which facilitates their movement across the mitochondrial membrane.[1]Once inside the mitochondria, these acylcarnitines, including decenoylcarnitine (a C10 medium-chain acylcarnitine), undergo beta-oxidation, a fundamental metabolic pathway that systematically breaks down fatty acids into acetyl-CoA, generating ATP and other energy intermediates.[1] This efficient catabolism of fatty acids is crucial for maintaining cellular energy homeostasis and providing fuel during periods of fasting or high energy demand.
Decenoylcarnitine, as a medium-chain acylcarnitine, directly participates in this mitochondrial beta-oxidation pathway, reflecting the cellular capacity to process medium-chain fatty acids.[1] Its presence and concentration are therefore indicative of the ongoing metabolic activity and the efficiency of fatty acid utilization within the cell. The precise balance of various acylcarnitine species highlights the intricate flux control within energy metabolism, where each type of fatty acid is processed through specific enzymatic steps.
Genetic Regulation of Beta-Oxidation Enzymes
Section titled “Genetic Regulation of Beta-Oxidation Enzymes”The initiation of fatty acid beta-oxidation is precisely regulated by a family of acyl-Coenzyme A dehydrogenases, which exhibit specificity for different fatty acid chain lengths. [1] For instance, SCAD (short-chain acyl-Coenzyme A dehydrogenase) is crucial for the oxidation of short-chain fatty acids, while MCAD(medium-chain acyl-Coenzyme A dehydrogenase) is specifically involved in the breakdown of medium-chain fatty acids, such as those that give rise to decenoylcarnitine.[1] Genetic variations within these enzyme-coding genes significantly influence their activity and, consequently, the metabolic flux through the beta-oxidation pathway.
Research indicates that specific intronic single nucleotide polymorphisms (SNPs) are strongly associated with altered acylcarnitine profiles.[1] For example, the SNP rs11161510 in the MCADgene is significantly linked to the ratio of medium-chain acylcarnitines, including C10 (decenoylcarnitine).[1] Similarly, rs2014355 in SCAD impacts short-chain acylcarnitine ratios, providing clear evidence of genetic regulation over the chain-length specific breakdown of fatty acids. [1] Individuals who are homozygous for the minor allele of these SNPs can exhibit reduced enzymatic turnover, leading to altered concentrations of their respective fatty acid substrates and products, thereby directly influencing the overall efficiency of fatty acid catabolism. [1]
Metabolic Signature and Systems Integration
Section titled “Metabolic Signature and Systems Integration”Acylcarnitine concentrations and their ratios in biological fluids serve as valuable metabolic phenotypes, offering a functional readout of an individual’s physiological state. [1] These “metabotypes” reflect the efficiency of specific metabolic reactions, such as fatty acid beta-oxidation, and are demonstrably influenced by genetic variants. [1] The strong associations observed between specific SNPs and metabolite ratios underscore how genetic architecture integrates with metabolic pathways, revealing underlying regulatory controls and potentially perturbed processes within the metabolic network. [1]
This systems-level integration highlights that changes in decenoylcarnitine levels are not isolated biochemical events but are interconnected with the broader network of lipid and energy metabolism.[1]Such comprehensive metabolic profiles offer profound insights into the complex interplay between genetic predispositions and overall metabolic function, influencing an individual’s biochemical landscape and contributing to emergent properties of health and disease.[1] Understanding these network interactions is key to deciphering how various metabolic pathways are coordinately regulated.
Disease Relevance and Genetic Predisposition
Section titled “Disease Relevance and Genetic Predisposition”Genetically determined metabotypes, including those reflected by specific acylcarnitine levels like decenoylcarnitine, play a significant role as discriminating cofactors in the etiology of common multi-factorial diseases.[1] Dysregulation in fatty acid oxidation, often influenced by genetic variants in key enzymes such as MCAD, can lead to altered metabolic profiles that impact an individual’s susceptibility to various conditions. [1]For instance, reduced dehydrogenase activity associated with minor allele homozygotes can result in an accumulation of longer-chain fatty acid substrates, potentially contributing to metabolic imbalances that underscore disease pathology.[1]
These metabolic variations, particularly when interacting with environmental factors like nutrition or lifestyle, can profoundly influence an individual’s predisposition to certain disease phenotypes.[1]Identifying such disease-relevant mechanisms, where genetic variations dictate metabolic flux and phenotypic expression, is crucial for advancing our understanding of disease pathogenesis and for developing targeted therapeutic strategies and personalized health interventions.
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, p. e1000282.
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[3] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, suppl. 1, 2007, p. S9.
[4] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.
[5] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, p. S2.
[6] 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, no. 1, 2008, pp. 139-49.
[7] Sabatti, C, et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 40, no. 12, 2008, pp. 1386-92.
[8] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-169.
[9] Maier, Elisabeth M., et al. “Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency.” Human Mutation, vol. 25, no. 5, 2005, pp. 443-452.