Dodecenoylcarnitine
Introduction
Section titled “Introduction”Dodecenoylcarnitine is a specific type of acylcarnitine, a class of molecules formed when fatty acids bind to carnitine. This binding is a crucial step in fatty acid metabolism, enabling the transport of fatty acids into the mitochondria where they undergo beta-oxidation to generate energy.[1]As a medium-chain acylcarnitine, dodecenoylcarnitine plays a role as a metabolic intermediate, and its levels in the body can reflect the efficiency of fatty acid processing. The study of such metabolites, known as metabolomics, aims to provide a comprehensive understanding of an individual’s physiological state by measuring endogenous metabolites.[1]
Biological Basis
Section titled “Biological Basis”The metabolism of dodecenoylcarnitine is intrinsically linked to enzymes involved in fatty acid beta-oxidation, particularly medium-chain acyl-Coenzyme A dehydrogenase (_MCAD_). _MCAD_ is an enzyme responsible for initiating the breakdown of medium-chain fatty acids. [1]Genetic variations, such as the intronic single nucleotide polymorphism (SNP)rs11161510 within the _MCAD_ gene, have been identified as strongly associated with the levels of medium-chain acylcarnitines. [1] Research suggests that individuals who are minor allele homozygotes for rs11161510 may experience reduced _MCAD_ enzymatic activity. This can lead to an accumulation of longer-chain fatty acid substrates relative to their shorter-chain products, thereby altering the balance of medium-chain acylcarnitines in the body. [1]
Clinical Relevance
Section titled “Clinical Relevance”Variations in dodecenoylcarnitine levels, often influenced by genetic factors, carry significant clinical implications. As a representative medium-chain acylcarnitine, its concentrations can serve as indicators of_MCAD_ function. Impaired _MCAD_ activity can be a hallmark of metabolic conditions, including medium-chain acyl-CoA dehydrogenase deficiency (MCADD), a disorder that can have serious health consequences. Understanding how genetic variants impact acylcarnitine profiles helps in identifying distinct metabolic phenotypes (metabotypes) that may confer susceptibility to various common multifactorial diseases. [1]Such genetically determined metabotypes are considered to be important contributing factors in disease etiology.[1]
Social Importance
Section titled “Social Importance”The investigation of dodecenoylcarnitine through advanced metabolomics and genome-wide association studies contributes significantly to the fields of personalized medicine and public health. By uncovering the genetic underpinnings that influence metabolite levels, researchers can develop a more nuanced understanding of the complex interactions between an individual’s genetic makeup, their metabolic processes, and their overall health.[1]This knowledge is crucial for developing strategies for early disease detection, implementing targeted preventive measures, and tailoring dietary or lifestyle interventions. Ultimately, these insights can empower individuals and healthcare providers to better manage health outcomes by considering how genetic and environmental factors collectively influence susceptibility to various health conditions.[1]
Limitations
Section titled “Limitations”Population Specificity and Generalizability
Section titled “Population Specificity and Generalizability”A significant limitation of existing research on dodecenoylcarnitine levels stems from the demographic homogeneity of the study populations. The primary discovery and replication cohorts predominantly comprised individuals of self-reported European ancestry. [2] While attempts were made to extend findings to multiethnic samples, such as those from Singapore which included Chinese, Malays, and Asian Indians [2] the overarching reliance on European populations limits the direct generalizability of the genetic associations to other ancestral groups. This narrow demographic focus means that the identified genetic variants and their effect sizes on dodecenoylcarnitine may not be directly transferable or fully representative in diverse global populations.
Furthermore, some cohorts were largely composed of middle-aged to elderly individuals, with DNA collection occurring at later examinations. [3] This age demographic introduces a potential survival bias, as only individuals who lived long enough to participate in these later assessments were included. Consequently, findings may not accurately reflect genetic influences on dodecenoylcarnitine in younger populations or individuals with different health trajectories, thereby further restricting the broader applicability of the research.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The ability to detect and confirm genetic associations with dodecenoylcarnitine is subject to several methodological and statistical limitations. Many studies faced challenges due to moderate cohort sizes, which limited their power to detect modest genetic effects and increased the susceptibility to false-negative findings, particularly given the extensive multiple testing inherent in genome-wide association studies. [3] The replication of findings across independent cohorts, considered the gold standard in genetic research [1] often proved challenging, with some meta-analyses indicating that only a fraction of associations were consistently replicated. [3] This suggests that some reported associations might represent false positives or context-specific effects, necessitating further validation.
Variations in genotyping platforms and the subsequent imputation of untyped single nucleotide polymorphisms (SNPs) across studies also introduced potential inaccuracies, with estimated error rates ranging from 1.46% to 2.14% per allele.[4] While meta-analyses were employed to synthesize findings, inconsistencies in analytical approaches, such as variations in covariate adjustment (e.g., inclusion of age2 or outlier exclusion) and the use of different statistical software [2] could affect the comparability and robustness of combined estimates. Although heterogeneity among studies was assessed, the reliance on fixed-effects meta-analysis models in some instances may not fully account for true biological or methodological differences across cohorts. [5]
Phenotypic Assessment and Confounding Variables
Section titled “Phenotypic Assessment and Confounding Variables”The accurate assessment of dodecenoylcarnitine levels and related phenotypes presents its own set of limitations. Phenotypic data were often subjected to transformations, such as log transformation for triglycerides, and multivariable adjustments for covariates like age, gender, and diabetes status. [2] In some cases, untreated lipid values were imputed, which introduces an additional layer of estimation that could influence the precision of genotype-phenotype associations. [2] A critical concern is the inconsistent availability of data regarding lipid-lowering therapy; for some cohorts, this information was unavailable and thus not considered in the analyses, potentially confounding genetic associations with dodecenoylcarnitine levels. [2]
Furthermore, the investigations largely did not delve into the complex interplay of gene-environmental interactions, which are known to modulate the effects of genetic variants on various phenotypes. [6]Environmental factors, such as dietary intake or lifestyle, can significantly influencedodecenoylcarnitine levels, and the absence of such analyses represents a substantial knowledge gap. Without exploring these interactions, the full biological context of genetic predispositions to dodecenoylcarnitine variation remains incompletely understood, limiting a comprehensive interpretation of the observed genetic effects.
Variants
Section titled “Variants”The ABCC1 (ATP Binding Cassette Subfamily C Member 1) gene encodes a protein known as Multidrug Resistance-associated Protein 1 (MRP1), a member of the ATP-binding cassette (ABC) transporter family. These proteins are crucial for pumping a wide range of substrates, including drugs, xenobiotics, and endogenous metabolites, out of cells, playing a significant role in detoxification and maintaining cellular homeostasis.[1] ABCC1 is widely expressed in various tissues and its activity can influence the bioavailability and elimination of many compounds, thereby impacting drug response and susceptibility to certain diseases. [1]
Variations within the ABCC1 gene, such as rs924138 , rs924136 , and rs35587 , can potentially alter the gene’s expression levels or the function of the MRP1 protein. These single nucleotide polymorphisms (SNPs) may reside in regulatory regions or introns, influencing how theABCC1 gene is transcribed or spliced, which in turn could lead to variations in the amount or activity of the MRP1 transporter protein. [1] Such changes in transporter function could affect the cellular efflux of its diverse substrates, potentially leading to altered intracellular concentrations of various molecules. [1]
While ABCC1is not directly recognized as a primary transporter for acylcarnitines, its broad substrate specificity and involvement in cellular efflux pathways suggest potential indirect implications for metabolites like dodecenoylcarnitine. Dodecenoylcarnitine is a medium-chain acylcarnitine (C12:0), an intermediate in fatty acid beta-oxidation, which is essential for energy production.[1] Alterations in ABCC1 activity due to variants like rs924138 , rs924136 , or rs35587 could indirectly impact the balance of cellular lipids or related metabolic intermediates by affecting the transport of other molecules that influence fatty acid metabolism or mitochondrial function. [1]
The impact of these ABCC1variants on dodecenoylcarnitine levels would likely stem from their influence on broader metabolic pathways rather than direct transport. Given the role of acylcarnitines in fatty acid transport and mitochondrial beta-oxidation, any genetic variations that perturb cellular energy metabolism or the handling of lipid-related compounds could have downstream effects on the concentrations of these crucial metabolites.[1] Therefore, variations in ABCC1 could contribute to subtle changes in metabolic profiles, potentially impacting conditions related to lipid metabolism or energy homeostasis. [1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs924138 rs924136 rs35587 | ABCC1 | metabolite measurement laurylcarnitine measurement succinylcarnitine measurement X-13431 measurement Cis-4-decenoyl carnitine measurement |
Causes of Dodecenoylcarnitine Levels
Section titled “Causes of Dodecenoylcarnitine Levels”Genetic Predisposition and Fatty Acid Metabolism
Section titled “Genetic Predisposition and Fatty Acid Metabolism”The concentration of dodecenoylcarnitine, a specific medium-chain acylcarnitine, is significantly influenced by genetic variations, contributing to individual differences in metabolic profiles.[1] Research indicates that frequent genetically determined metabotypes play a role as discriminating cofactors in the etiology of common multifactorial diseases, with specific genetic loci impacting the homeostasis of key lipids and metabolites. [1] A prime example is the strong association observed between the intronic SNP rs11161510 within the MCAD(medium-chain acyl-Coenzyme A dehydrogenase) gene on chromosome 1 and the ratio of various medium-chain acylcarnitines, including dodecenoylcarnitine.[1]
The MCAD gene encodes a critical enzyme responsible for initiating the beta-oxidation of fatty acids, a fundamental process for energy production within mitochondria. [1] Variations in this gene can directly impair enzyme function; for instance, minor allele homozygotes of rs11161510 demonstrate a reduced enzymatic turnover in these reactions. [1] This diminished MCADactivity leads to an accumulation of its substrates, such as longer-chain fatty acids and their acylcarnitine forms like dodecenoylcarnitine, thereby altering the metabolic balance and reflecting an underlying genetic influence on lipid processing.[1]
Interaction with Lifestyle and Nutritional Factors
Section titled “Interaction with Lifestyle and Nutritional Factors”While specific environmental factors directly influencing dodecenoylcarnitine levels are not extensively detailed, research indicates that genetically determined metabotypes, such as those impacting fatty acid metabolism, can interact with environmental factors.[1]Lifestyle choices and nutritional intake are recognized as key environmental influences that can modulate an individual’s susceptibility to various phenotypes.[1]This suggests that dietary composition, particularly the intake of different types of fatty acids, or other lifestyle elements could potentially modify the impact ofMCADgenetic variants on dodecenoylcarnitine levels, though the precise mechanisms require further elucidation.[1]
Biological Background
Section titled “Biological Background”Fatty Acid Metabolism and the Carnitine Shuttle
Section titled “Fatty Acid Metabolism and the Carnitine Shuttle”Dodecenoylcarnitine is a medium-chain acylcarnitine, a class of molecules critical for the cellular metabolism of fatty acids. Fatty acids serve as a primary energy source, particularly during periods of fasting or high energy demand. To be utilized for energy, fatty acids must undergo beta-oxidation within the mitochondria, a process that breaks them down into acetyl-CoA units. However, fatty acids cannot freely cross the inner mitochondrial membrane; instead, they are bound to free carnitine to form acylcarnitines, which are then transported into the mitochondria via the carnitine shuttle system.[1] This intricate transport mechanism ensures the efficient delivery of fatty acids to the mitochondrial matrix, where beta-oxidation commences, playing a vital role in cellular energy homeostasis.
The Role of Acyl-CoA Dehydrogenases in Beta-Oxidation
Section titled “The Role of Acyl-CoA Dehydrogenases in Beta-Oxidation”Once inside the mitochondria, acylcarnitines are converted back to acyl-CoAs, which then enter the beta-oxidation pathway, initiated by a family of acyl-Coenzyme A dehydrogenases. These enzymes are specific to fatty acid chain length, with the medium-chain acyl-Coenzyme A dehydrogenase (MCAD) being particularly relevant for dodecenoylcarnitine.MCAD catalyzes the first step of beta-oxidation for medium-chain fatty acids, converting them into enoyl-CoAs. [1] The efficiency of MCADdirectly influences the balance of medium-chain acylcarnitines; a reduced activity of this enzyme can lead to an accumulation of its substrates, such as dodecenoylcarnitine, while decreasing the production of shorter-chain products.[1]
Genetic Influences on Lipid Metabolism
Section titled “Genetic Influences on Lipid Metabolism”Genetic variations significantly impact the efficiency of metabolic enzymes and, consequently, circulating metabolite profiles. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding acyl-CoA dehydrogenases, such asMCAD, that are associated with distinct acylcarnitine concentrations. [1] For instance, the intronic SNP rs11161510 in the MCAD gene has been linked to ratios of medium-chain acylcarnitines, implying that minor allele homozygotes may have lower enzymatic turnover for these reactions. [1] Such genetic predispositions, termed “metabotypes,” can alter an individual’s metabolic landscape and influence their susceptibility to common multifactorial diseases. [1]
Dodecenoylcarnitine as a Metabolic Biomarker and Pathophysiological Relevance
Section titled “Dodecenoylcarnitine as a Metabolic Biomarker and Pathophysiological Relevance”Variations in dodecenoylcarnitine levels, reflective of the efficiency of fatty acid beta-oxidation, can serve as metabolic biomarkers. Disruptions in fatty acid metabolism, whether due to genetic factors or environmental influences, can lead to homeostatic imbalances with systemic consequences. Altered acylcarnitine profiles are often observed in conditions related to lipid dysregulation and have been implicated in the pathophysiology of diseases such as coronary artery disease (CAD).[4]These genetically determined metabotypes, by influencing lipid concentrations and metabolic pathways, can interact with lifestyle and nutritional factors to modulate an individual’s risk for various phenotypes, including cardiovascular health outcomes.[1]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Mitochondrial Fatty Acid Beta-Oxidation and Carnitine Shuttle
Section titled “Mitochondrial Fatty Acid Beta-Oxidation and Carnitine Shuttle”Dodecenoylcarnitine, as a medium-chain acylcarnitine, plays a pivotal role in the mitochondrial beta-oxidation pathway, which is essential for cellular energy production. Fatty acids are bound to free carnitine for transport into the mitochondria, forming acylcarnitines that can cross the inner membrane.[1]This carnitine shuttle system facilitates the subsequent breakdown of fatty acids, including dodecenoic acid, to generate ATP through catabolism.[1]Thus, dodecenoylcarnitine serves as a crucial intermediate, enabling the efficient utilization of medium-chain fatty acids as a vital energy source within the cell.
Genetic Modulators of Acylcarnitine Levels
Section titled “Genetic Modulators of Acylcarnitine Levels”The concentrations of dodecenoylcarnitine and other medium-chain acylcarnitines are significantly influenced by genetic variations that impact the activity of enzymes involved in fatty acid beta-oxidation. Polymorphisms within theMCAD (medium-chain acyl-Coenzyme A dehydrogenase) gene, such as rs11161510 , are strongly associated with the ratio of medium-chain acylcarnitines, directly affecting enzymatic turnover. [1] Similarly, genetic variants in SCAD (short-chain acyl-Coenzyme A dehydrogenase), exemplified by rs2014355 , influence short-chain acylcarnitine ratios, collectively demonstrating how genetic factors regulate metabolic flux through these critical catabolic pathways. [1] Individuals homozygous for minor alleles in these genes often exhibit reduced dehydrogenase activity, leading to higher concentrations of longer-chain fatty acid substrates and consequently altering their metabolic profiles. [1]
Metabolic Regulation and Systemic Lipid Homeostasis
Section titled “Metabolic Regulation and Systemic Lipid Homeostasis”The pathways involving dodecenoylcarnitine are intricately integrated into broader systemic lipid homeostasis, which is controlled by complex regulatory mechanisms. Genes such asANGPTL3 and ANGPTL4are known to regulate overall lipid metabolism, impacting circulating triglyceride and high-density lipoprotein (HDL) levels, which in turn influences the availability of fatty acids for carnitine-mediated transport and oxidation.[7] Furthermore, transcription factors like SREBP-2 regulate the mevalonate pathway, establishing a link between isoprenoid and adenosylcobalamin metabolism, and highlighting the interconnectedness of various lipid and energy metabolic routes. [8] This hierarchical regulation ensures a coordinated cellular response to nutrient availability and energy demands, where acylcarnitine levels serve as dynamic indicators of the metabolic state.
Implications for Cardiometabolic Health
Section titled “Implications for Cardiometabolic Health”Dysregulation within the metabolic pathways involving dodecenoylcarnitine can have significant consequences for cardiometabolic health and contribute to the etiology of common multifactorial diseases. Genetically determined “metabotypes,” characterized by specific acylcarnitine profiles influenced by variants in genes likeMCAD, are thought to act as discriminating cofactors that modulate an individual’s susceptibility to certain phenotypes. [1]These altered metabolic states, particularly those affecting lipid concentrations and energy metabolism, are directly relevant to the risk of coronary artery disease and polygenic dyslipidemia.[4]Understanding these pathway dysregulations and any compensatory mechanisms they trigger provides potential avenues for therapeutic interventions aimed at restoring metabolic balance and mitigating disease risk.
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.
[2] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 12, 2008, pp. 1417-24.
[3] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, 2007, p. 64.
[4] 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. 161-9.
[5] 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. 5, 2008, pp. 520-8.
[6] 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, 2007, p. 66.
[7] Koishi, Ryo, et al. “Angptl3 regulates lipid metabolism in mice.” Nat Genet, vol. 30, no. 2, 2002, pp. 151–157.
[8] Murphy, Clare, et al. “Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.” Biochem Biophys Res Commun, vol. 355, no. 2, 2007, pp. 359–364.