Butyrylcarnitine
Butyrylcarnitine, often referred to as C4 acylcarnitine, is a short-chain acylcarnitine that plays a crucial role in the body’s metabolism. Acylcarnitines are a class of molecules formed when fatty acids are bound to L-carnitine, a naturally occurring compound. This binding is essential for transporting fatty acids across mitochondrial membranes, where they undergo beta-oxidation to produce energy. Butyrylcarnitine specifically represents a fatty acid with a four-carbon chain that has been conjugated with carnitine.
Biological Basis
Section titled “Biological Basis”The formation and metabolism of butyrylcarnitine are intimately linked to the process of fatty acid beta-oxidation within the mitochondria. Fatty acids, including short-chain ones like butyric acid, are converted into acyl-Coenzyme A (acyl-CoA) molecules. These acyl-CoAs then bind to free carnitine to form acylcarnitines, enabling their entry into the mitochondrial matrix for further breakdown.[1] An enzyme called short-chain acyl-Coenzyme A dehydrogenase (SCAD) is particularly important in initiating the beta-oxidation of short-chain fatty acids. Genetic variations, such as the intronic single nucleotide polymorphismrs2014355 in the SCAD gene, have been strongly associated with levels of short-chain acylcarnitines. [1]Specifically, this polymorphism has been found to associate with the ratio between C3 (propionylcarnitine) and C4 (butyrylcarnitine) acylcarnitines.[1] Studies suggest that individuals with certain minor allele homozygotes for these polymorphisms may exhibit reduced enzymatic turnover for these reactions, leading to altered concentrations of these metabolites. [1]
Clinical Relevance
Section titled “Clinical Relevance”The levels of butyrylcarnitine and other acylcarnitines can serve as indicators of metabolic health and the efficiency of fatty acid oxidation. Imbalances in these metabolites can point to underlying issues in energy production or the breakdown of fats. Genetic variations affecting enzymes likeSCAD, which influence butyrylcarnitine levels, are considered to contribute to what are known as “genetically determined metabotypes.” These metabotypes are thought to act as discriminating cofactors in the development of common multifactorial diseases.[1]Understanding these genetic influences on metabolite profiles provides insights into an individual’s physiological state and potential susceptibility to various health conditions, particularly those related to metabolic disorders.[1]
Social Importance
Section titled “Social Importance”The study of butyrylcarnitine and its genetic determinants is part of the broader field of metabolomics, which aims to comprehensively measure metabolites in biological samples. By linking genetic variants to metabolite profiles, researchers can better understand how an individual’s genetic makeup interacts with environmental factors, such as diet and lifestyle, to influence their health outcomes.[1] This knowledge has the potential to advance personalized medicine by identifying individuals at higher risk for certain conditions based on their unique metabolic and genetic profiles, potentially leading to more targeted prevention and treatment strategies.
Limitations
Section titled “Limitations”Methodological and Statistical Rigor
Section titled “Methodological and Statistical Rigor”The interpretation of genetic associations with butyrylcarnitine levels is subject to several methodological and statistical limitations inherent in genome-wide association studies (GWAS). Many studies, particularly those with moderate sample sizes, may lack sufficient statistical power to detect genetic effects that contribute only modestly to the overall phenotypic variation, potentially leading to false negative findings. [2] Conversely, the extensive multiple testing performed in GWAS increases the likelihood of observing false positive associations, necessitating rigorous replication in independent cohorts to validate initial discoveries. [3] The process of replication itself can be complex, as non-replication might stem from false positive initial findings, differences in cohort characteristics, or inadequate statistical power in replication studies. [2] Furthermore, reliance on imputed genotypes introduces a degree of error, though generally low, which can impact the accuracy of association signals. [4]
Generalizability and Phenotypic Measurement
Section titled “Generalizability and Phenotypic Measurement”A significant limitation concerns the generalizability of findings for butyrylcarnitine and other traits, as many discovery and replication cohorts are predominantly composed of individuals of white European ancestry. [5] This lack of ethnic diversity means that results may not be directly applicable to populations with different genetic backgrounds or environmental exposures, limiting broader clinical or public health relevance. [3] Additionally, the definition and measurement of phenotypes can introduce bias; for instance, collecting DNA at later examination points might introduce survival bias. [2] When phenotypes are averaged over long periods, such as twenty years, potential misclassification can arise from changes in measurement equipment, and the assumption that similar genes and environmental factors influence traits across a wide age range may mask age-dependent genetic effects. [6] Inconsistencies in accounting for confounding factors, such as the use of lipid-lowering therapies, or the reliance on proxy markers when direct measurements are unavailable, can further complicate the interpretation of genetic associations. [3]
Environmental and Genetic Interaction Gaps
Section titled “Environmental and Genetic Interaction Gaps”Current research on butyrylcarnitine often does not fully explore the intricate interplay between genetic variants and environmental factors, despite evidence that genetic effects can be context-specific and modulated by environmental influences. [6]The omission of gene-environment interaction analyses limits a comprehensive understanding of how genetic predispositions manifest under varying lifestyle or environmental conditions.[6]Furthermore, studies focusing solely on multivariable models might overlook important bivariate associations, and residual confounding from unmeasured environmental or lifestyle variables could still influence observed genetic associations.[3] The broader challenge of “missing heritability” persists, indicating that a substantial portion of the genetic variance for complex traits like butyrylcarnitine levels remains unexplained by identified common variants, highlighting the need for further investigation into rare variants, structural variations, or more complex genetic architectures. [7]
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing an individual’s metabolic profile, including levels of acylcarnitines like butyrylcarnitine, which is a marker of short-chain fatty acid oxidation. Several genes and their associated variants are implicated in pathways directly and indirectly affecting butyrylcarnitine concentrations. These include enzymes vital for fatty acid breakdown, solute transporters, and regulatory elements.
Genes such as _ACADS_ and _ETFA_ are central to the mitochondrial beta-oxidation pathway, which is responsible for breaking down fatty acids into energy. _ACADS_ (Acyl-CoA Dehydrogenase, Short Chain) is an enzyme specifically catalyzing the first step in the oxidation of short-chain fatty acids, producing butyryl-CoA. Variants like rs1800556 , rs2014355 , and rs1799958 in _ACADS_can impact the enzyme’s efficiency, potentially leading to an accumulation of butyrylcarnitine if fatty acid breakdown is impaired..[1] Similarly, _ETFA_ (Electron Transfer Flavoprotein, Alpha Subunit) forms part of a complex that transfers electrons from various acyl-CoA dehydrogenases, including _ACADS_, to the electron transport chain. Genetic variations such as rs71140202 and rs78185702 in _ETFA_could disrupt this electron transfer, thereby hindering the overall fatty acid oxidation process and consequently affecting butyrylcarnitine levels..[4]
The transport of carnitine and acylcarnitines across cell membranes is largely managed by the_SLC_ (Solute Carrier) gene family. Members like _SLC22A1_, _SLC22A4_, and _SLC22A5_are organic cation and anion transporters that facilitate the movement of various endogenous compounds, including carnitine and its derivatives like butyrylcarnitine, in tissues such as the kidney and liver. Variants such asrs662138 , rs34130495 in _SLC22A1_, rs200800380 , rs272885 , rs272879 in _SLC22A4_, and rs386134194 in _SLC22A5_could alter the transport capabilities of these proteins, influencing the systemic concentrations and excretion of butyrylcarnitine..[8] _SLC16A9_, a monocarboxylate transporter, with variants rs1171617 and rs1171616 , may also indirectly affect butyrylcarnitine by influencing the transport of short-chain fatty acids or related metabolic precursors..[1] The long non-coding RNA _MIR3936HG_, located near _SLC22A4_, also has variants like rs200800380 , rs272885 , and rs272879 that might exert regulatory effects on neighboring genes, including _SLC22A4_, thereby impacting transport processes relevant to butyrylcarnitine.
Other genes also contribute to the complex regulation of metabolic processes that can influence butyrylcarnitine levels._UNC119B_, for example, is a lipid-binding protein involved in G protein-coupled receptor signaling, which often plays a role in lipid metabolism and cellular communication. The variant rs2066938 in _UNC119B_might affect its lipid-binding capacity or regulatory function, indirectly influencing pathways related to fatty acid oxidation or carnitine homeostasis..[4] Similarly, _ZNF22-AS1_ is an antisense long non-coding RNA, whose variant rs199544621 could modulate the expression of nearby genes. Such regulatory effects can ripple through metabolic networks, potentially altering the activity of enzymes or transporters involved in butyrylcarnitine metabolism..[1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2066938 | UNC119B | metabolite measurement serum metabolite level protein measurement butyrylcarnitine measurement ethylmalonate measurement |
| rs1171617 rs1171616 | SLC16A9 | carnitine measurement urate measurement gout testosterone measurement X-11261 measurement |
| rs662138 rs34130495 | SLC22A1 | metabolite measurement serum metabolite level apolipoprotein B measurement aspartate aminotransferase measurement total cholesterol measurement |
| rs78185702 | ETFA - ISL2 | dimethylglycine measurement ethylmalonate measurement isovalerylcarnitine measurement butyrylcarnitine measurement glutarylcarnitine (C5-DC) measurement |
| rs200800380 rs272885 | MIR3936HG, SLC22A4 | butyrylcarnitine measurement platelet count serum creatinine amount |
| rs71140202 | ETFA | butyrylcarnitine measurement |
| rs272879 | SLC22A4, MIR3936HG | butyrylcarnitine measurement |
| rs386134194 | SLC22A5 | carnitine measurement acetylcarnitine measurement butyrylcarnitine measurement |
| rs199544621 | ZNF22-AS1 | butyrylcarnitine measurement |
| rs1800556 rs2014355 rs1799958 | ACADS | butyrylcarnitine measurement serum metabolite level cerebrospinal fluid composition attribute, ethylmalonate measurement butyrylcarnitine (C4) measurement ethylmalonate measurement |
Biological Background
Section titled “Biological Background”Metabolic Pathways and Molecular Regulation
Section titled “Metabolic Pathways and Molecular Regulation”The human body maintains a complex homeostasis of various endogenous metabolites, including key lipids, carbohydrates, and amino acids, with deviations often reflecting physiological states. [1] Metabolic processes are tightly regulated by a network of critical proteins and enzymes. For instance, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a central role in cholesterol synthesis via the mevalonate pathway, with its activity directly influencing cellular cholesterol levels and compensatory uptake mechanisms. [7]Similarly, lipoprotein lipase activity, crucial for lipid processing, is modulated by proteins likeSortilin/neurotensin receptor-3, which mediates its degradation. [9]
Beyond lipid synthesis, broader metabolic control involves transcription factors such as SREBP-2, which links isoprenoid and adenosylcobalamin metabolism. [10] Other regulatory proteins, like Angptl3 and ANGPTL4, are known to influence lipid metabolism, specifically affecting triglyceride levels and high-density lipoprotein (HDL) concentrations.[11] Cellular signaling pathways, including mitogen-activated protein kinase (MAPK) cascades regulated by Tribbles proteins, also contribute to the intricate control of metabolic functions and cellular responses. [12]
Genetic Mechanisms and Expression Patterns
Section titled “Genetic Mechanisms and Expression Patterns”Genetic variations significantly influence metabolic profiles and the activity of key biomolecules. Genome-wide association studies have identified common genetic variations near genes like MC4R and MLXIPLthat are associated with metabolic traits such as waist circumference, insulin resistance, and plasma triglycerides.[13]The expression and function of metabolic enzymes can also be regulated through sophisticated genetic mechanisms, including alternative splicing. For example, common single nucleotide polymorphisms (SNPs) inHMGCR can affect the alternative splicing of its exon 13, leading to altered HMGCR messenger RNA (mRNA) levels and influencing LDL-cholesterol concentrations. [7]
Alternative splicing represents a crucial post-transcriptional regulatory mechanism, with genetic variants impacting its patterns and consequently affecting protein isoforms and cellular functions. [14] Beyond splicing, gene mutations can have profound effects, as seen with a null mutation in APOC3 that confers a favorable plasma lipid profile and offers cardioprotection. [15] Furthermore, genes like SLC2A9function as urate transporters, with variations influencing serum urate concentrations and the risk of gout.[8]
Pathophysiological Processes and Systemic Consequences
Section titled “Pathophysiological Processes and Systemic Consequences”Disruptions in metabolic homeostasis are central to various pathophysiological processes, impacting multiple tissues and organs. Altered lipid concentrations, often influenced by genetic factors, are strongly linked to the risk of coronary artery disease and dyslipidemia.[4]Conditions like insulin resistance and type 2 diabetes are associated with genetic variations in metabolic pathways, including those involving glucokinase andMC4R. [16] At the organ level, the liver plays a critical role in metabolism, and genetic loci can influence plasma levels of liver enzymes. [17]
Cardiovascular health is particularly sensitive to metabolic imbalances, with mutations in genes likePRKAG2leading to cardiac hypertrophy and conduction system disturbances, such as Wolff-Parkinson-White syndrome.[6] Similarly, the cardiac ryanodine receptor gene (RYR2) is fundamental to calcium trafficking during myocardial excitation-contraction coupling, and its mutations can underlie exercise-induced ventricular tachyarrhythmias.[18] Beyond the heart, systemic inflammation, regulated in part by proteins like Carboxypeptidase N, and vascular smooth muscle cell function, influenced by agents like Angiotensin II andSlit2, also reflect broader metabolic and cellular health. [19]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Pathways of Butyrylcarnitine
Section titled “Metabolic Pathways of Butyrylcarnitine”Butyrylcarnitine (C4 acylcarnitine) is a key metabolite within the broader context of fatty acid beta-oxidation, the primary cellular pathway for generating energy from fats. This process necessitates that fatty acids, including short-chain varieties like butyrate, are conjugated to free carnitine for efficient transport into the mitochondrial matrix, where beta-oxidation commences.[1] A pivotal enzyme in this pathway is short-chain acyl-Coenzyme A dehydrogenase (SCAD), which catalyzes an initial step in the breakdown of short-chain fatty acids by converting their acyl-CoA esters into corresponding enoyl-CoAs. [1]Consequently, butyrylcarnitine, alongside propionylcarnitine (C3 acylcarnitine), serves as an indicator ofSCAD activity and the overall flux through the initial stages of short-chain fatty acid catabolism. [1]
Genetic Regulation of Acylcarnitine Metabolism
Section titled “Genetic Regulation of Acylcarnitine Metabolism”The efficiency and regulation of butyrylcarnitine metabolism are significantly influenced by genetic factors. Research indicates that specific single nucleotide polymorphisms (SNPs) can impact the activity of enzymes crucial for acylcarnitine processing. For instance, an intronic SNP,rs2014355 , located within the SCAD gene on chromosome 12, shows a strong association with the ratio of short-chain acylcarnitines C3 and C4. [1] Individuals who are minor allele homozygotes for this variant exhibit a reduced enzymatic turnover for SCAD-mediated reactions, suggesting a direct link between gene regulation, protein function, and the steady-state concentrations of these important metabolic intermediates. [1]
Systems-Level Integration in Lipid Metabolism
Section titled “Systems-Level Integration in Lipid Metabolism”Butyrylcarnitine metabolism is not an isolated process but is deeply integrated into the complex network of systemic lipid homeostasis and energy balance. Metabolomics studies comprehensively profile endogenous metabolites, offering a functional readout of an organism’s physiological state and revealing how genetic variants can perturb the delicate equilibrium of lipids, carbohydrates, and amino acids.[1] Changes in acylcarnitine profiles, such as those caused by altered SCAD activity, can reflect broader shifts in fatty acid oxidation, a fundamental energy metabolism pathway that interacts with cholesterol synthesis (e.g., the mevalonate pathway involving HMGCR and SREBP-2) and triglyceride regulation (e.g., viaMLXIPL, ANGPTL3, and ANGPTL4). [7] This intricate pathway crosstalk underscores how metabolic adjustments in one area can reverberate throughout the entire metabolic system.
Butyrylcarnitine in Metabolic Health and Disease
Section titled “Butyrylcarnitine in Metabolic Health and Disease”Dysregulation of butyrylcarnitine metabolism, often driven by underlying genetic predispositions, plays a role in the etiology of complex multifactorial diseases. Genetically determined metabotypes, which describe distinct metabolic profiles, act as significant cofactors influencing an individual’s susceptibility to various health phenotypes.[1] For example, impaired SCAD activity, indicated by altered C3/C4 acylcarnitine ratios linked to specific genetic variants, can lead to less efficient short-chain fatty acid oxidation and potentially contribute to metabolic imbalances. [1]Such pathway dysregulation is relevant in the context of broader metabolic conditions, including those affecting lipid concentrations, insulin resistance, and liver enzyme levels, which are frequently investigated through large-scale genome-wide association studies.[17]
References
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[7] 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, vol. 29, 2009, pp. 1880–2019.
[8] Vitart V, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008 April;40(4):432-436.
[9] Nielsen, M.S., et al. “Sortilin/neurotensin receptor-3binds and mediates degradation of lipoprotein lipase.”J Biol Chem, vol. 274, 1999, pp. 8832–8836.
[10] Murphy, C., et al. “Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.” Biochem Biophys Res Commun, vol. 355, 2007, pp. 359–364.
[11] Koishi, R., et al. “Angptl3 regulates lipid metabolism in mice.” Nat Genet, vol. 30, 2002, pp. 151–157.
[12] Kiss-Toth, E., et al. “Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.” J Biol Chem, vol. 279, 2004, pp. 42703–42708.
[13] Chambers, J.C., et al. “Common genetic variation near MC4Ris associated with waist circumference and insulin resistance.”Nat Genet, vol. 40, 2008, pp. 716–718.
[14] Johnson, J.M., et al. “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.” Science, vol. 302, 2003, pp. 2141–2144.
[15] Pollin, T.I., et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, 2008, pp. 1702–1705.
[16] Garcia-Herrero, C.M., et al. “Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.”Diabetologia, vol. 50, 2007, pp. 325–333.
[17] 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, 2008, pp. 520–528.
[18] Priori, S.G., et al. “Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polyventricular Tachycardia.” Circulation, vol. 103, 2001, pp. 196–200.
[19] Matthews, K.W., et al. “Carboxypeptidase N: A pleiotropic regulator of inflammation.” Mol Immunol, vol. 40, 2004, pp. 785–793.