Hexadecenoylcarnitine
Introduction
Section titled “Introduction”Hexadecenoylcarnitine is an acylcarnitine, a class of molecules formed when fatty acids are esterified to carnitine. These molecules play a crucial role in the transport and metabolism of fatty acids within the body. Specifically, hexadecenoylcarnitine (often denoted as C16:1-carnitine) is involved in the mitochondrial beta-oxidation of long-chain monounsaturated fatty acids.
Biological Basis
Section titled “Biological Basis”Carnitine acts as a shuttle, transporting fatty acids from the cytosol into the mitochondria, where they undergo beta-oxidation to produce energy. This process is facilitated by the carnitine palmitoyltransferase (CPT) system. Hexadecenoylcarnitine represents a specific intermediate in this pathway, indicating the presence and utilization of 16-carbon fatty acids with one double bond. The levels of various acylcarnitines in bodily fluids can reflect the efficiency of fatty acid metabolism and the activity of related enzymatic pathways. The field of metabolomics aims to comprehensively measure endogenous metabolites in body fluids, providing a functional readout of physiological states and identifying genetic variants that associate with changes in the homeostasis of key lipids, carbohydrates, or amino acids.[1]
Clinical Relevance
Section titled “Clinical Relevance”Abnormal levels of hexadecenoylcarnitine can be indicative of underlying metabolic disorders, particularly those affecting fatty acid oxidation. These disorders can lead to an accumulation of specific acylcarnitines, which can be detected through newborn screening programs. Imbalances in lipid metabolism, including the processing of fatty acids, are also linked to broader health conditions such as dyslipidemia and cardiovascular disease. Genome-wide association studies (GWAS) have identified numerous genetic variants that contribute to polygenic dyslipidemia and influence plasma lipid levels, including low-density lipoprotein cholesterol (LDL-C).[2]Understanding the role of specific metabolites like hexadecenoylcarnitine in these complex traits, often through metabolomics-driven GWAS, can provide insights into disease mechanisms and potential therapeutic targets.[1] For instance, genetic variations in genes like HMGCR, which is central to cholesterol synthesis, have been linked to LDL-C levels and alternative splicing patterns that affect enzyme activity. [3]
Social Importance
Section titled “Social Importance”The study of hexadecenoylcarnitine and other metabolites holds significant social importance through its implications for diagnostics, personalized medicine, and public health. Early detection of fatty acid oxidation disorders via acylcarnitine profiling can prevent severe health consequences in affected individuals. Furthermore, by linking genetic variations to specific metabolite profiles, researchers can identify individuals at higher risk for metabolic diseases and develop more targeted interventions. The broader understanding of how genetic factors influence lipid and energy metabolism, as revealed by studies integrating genetics and metabolomics, contributes to a more comprehensive view of human health and disease.[1]
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Genetic association studies, particularly those involving a large number of genetic markers and phenotypes, often face limitations in statistical power to detect genetic effects that explain only a small proportion of phenotypic variation. While some studies achieve high power for effects explaining 4% or more of variation, more modest genetic influences may remain undetected, requiring larger sample sizes or more targeted approaches
Variants
Section titled “Variants”Genetic variations can significantly influence metabolic pathways, including the processing of fatty acids and acylcarnitines like hexadecenoylcarnitine. The solute carrier family 22 member 5,_SLC22A5_, is a gene crucial for the transport of carnitine, a molecule essential for shuttling fatty acids into the mitochondria for beta-oxidation. This process is vital for energy production, and disruptions can lead to altered levels of various acylcarnitines, including hexadecenoylcarnitine (C16:1-carnitine), which is a long-chain acylcarnitine. The single nucleotide polymorphism (SNP)*rs2073643 * may impact the function or expression of _SLC22A5_, potentially affecting the efficiency of carnitine transport and, consequently, the metabolism of fatty acids and the circulating levels of hexadecenoylcarnitine..[1]The proper transport of fatty acids, bound to free carnitine, into the mitochondrion is a prerequisite for their breakdown and energy release..[1]
The _P4HA2_ gene encodes prolyl 4-hydroxylase, alpha polypeptide II, an enzyme that plays a critical role in the synthesis of collagen by hydroxylating proline residues. This hydroxylation is essential for the stability and proper folding of the collagen triple helix, a fundamental component of connective tissues throughout the body. While primarily known for its role in structural integrity, collagen metabolism can be indirectly linked to overall cellular health and metabolic processes. A variant such as *rs10479000 *, if located within or near _P4HA2_, could potentially influence the enzyme’s activity or expression, which might have downstream effects on cellular function and energy homeostasis, broadly impacting lipid metabolism and potentially hexadecenoylcarnitine levels. Genome-wide association studies have identified numerous DNA variants that influence various human diseases and metabolic traits..[4]
Another gene, _PDLIM4_(PDZ and LIM domain protein 4), acts as a scaffolding protein involved in organizing protein complexes at specific cellular locations, influencing cell structure, signaling pathways, and potentially gene expression. While a direct link to hexadecenoylcarnitine is not immediately evident, proteins like_PDLIM4_ are integral to cellular regulation. Variations in such genes could subtly alter cell signaling or structural integrity, which might indirectly affect metabolic pathways, including those involved in lipid processing. The broader context of metabolomics research demonstrates that genetic variations can lead to diverse metabolic phenotypes, including alterations in phospholipid concentrations and other lipid-related traits.. [1]Such systemic changes could, in turn, influence the balance of acylcarnitines like hexadecenoylcarnitine, reflecting a wider impact on cellular energy metabolism.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs10479000 | P4HA2, PDLIM4 | health trait hexadecenoylcarnitine measurement linoleoylcarnitine (C18:2) measurement grip strength measurement |
| rs2073643 | SLC22A5 | asthma mosquito bite reaction size measurement hexadecenoylcarnitine measurement erythrocyte attribute |
Biological Background
Section titled “Biological Background”Acylcarnitines and Lipid Metabolic Pathways
Section titled “Acylcarnitines and Lipid Metabolic Pathways”Hexadecenoylcarnitine is identified as an acylcarnitine, a class of metabolites detected in human serum as part of comprehensive metabolomics studies.[1] These molecules are integral to the cellular metabolism of lipids, primarily by facilitating the transport of long-chain fatty acids into the mitochondrial matrix, where they undergo beta-oxidation to produce energy. [1]The specific composition and concentration of acylcarnitines, such as hexadecenoylcarnitine (C16:1), provide a functional readout of the body’s physiological state, reflecting the efficiency and balance of fatty acid processing pathways.[1] Imbalances in these metabolic processes can significantly impact overall lipid homeostasis, affecting the availability of fatty acids for energy production or storage, and thus influencing various cellular functions across different tissues.
Genetic Regulation of Lipid Metabolism
Section titled “Genetic Regulation of Lipid Metabolism”The intricate balance of lipid metabolism, encompassing acylcarnitine levels and other lipid concentrations, is profoundly influenced by underlying genetic mechanisms. Common genetic variations, including single nucleotide polymorphisms (SNPs), can modulate the function and expression patterns of genes crucial to lipid pathways[2], [3], [5]. [6] For instance, SNPs within the HMGCR gene, which encodes 3-hydroxy-3-methylglutaryl coenzyme A reductase, can impact the alternative splicing of exon13, leading to altered enzymatic activity and subsequent changes in cholesterol synthesis. [3] This genetic modulation, whether through transcriptional regulation or alternative splicing, contributes to the observed inter-individual variability in lipid concentrations and shapes the body’s metabolic landscape. [3] Other genes, such as ANGPTL3, ANGPTL4, LPL, MLXIPL, and the FADS1/FADS2 gene cluster, are also associated with various lipid levels, underscoring the complexity of this genetic regulatory network [7], [8]. [2]
Key Biomolecules and Their Cellular Functions
Section titled “Key Biomolecules and Their Cellular Functions”The complex processes of lipid metabolism are orchestrated by several critical biomolecules, including enzymes, receptors, and transcription factors. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is central to cholesterol biosynthesis, with its activity meticulously regulated at multiple levels, including through alternative splicing. [3] Lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) are essential for the processing of lipoproteins and the remodeling of high-density lipoprotein (HDL) particles[2]. [9]Regulatory proteins such as ANGPTL3 and ANGPTL4 play significant roles in modulating lipid metabolism, influencing circulating triglyceride levels and HDL concentrations[7]. [8] Furthermore, transcription factors like sterol regulatory element-binding protein 2 (SREBP-2) and hepatocyte nuclear factors, specifically HNF4A and HNF1A, are vital in controlling the expression of genes involved in cholesterol, bile acid, and overall lipid homeostasis, particularly within the liver [10], [11], [12]. [13]
Systemic Lipid Homeostasis and Pathophysiological Implications
Section titled “Systemic Lipid Homeostasis and Pathophysiological Implications”The coordinated activity of these molecular and cellular pathways is essential for maintaining systemic lipid homeostasis, a critical aspect of overall health. The liver plays a predominant role in this process, regulating cholesterol synthesis, lipoprotein production, and bile acid metabolism[10], [12]. [13]Disruptions in this delicate balance, often exacerbated by genetic predispositions, can lead to pathophysiological conditions such as dyslipidemia, characterized by abnormal levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides[5]. [2]These lipid imbalances are well-established risk factors for chronic cardiovascular diseases, including coronary artery disease[5]. [14] The body attempts to compensate for these disruptions, for instance, by increasing cholesterol uptake from the plasma via the LDL-receptor pathway when cellular cholesterol synthesis is reduced, in an effort to restore intracellular cholesterol balance. [3]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Flux and Fatty Acid Oxidation
Section titled “Metabolic Flux and Fatty Acid Oxidation”The metabolism of hexadecenoylcarnitine is intricately linked to the broader fatty acid oxidation pathway, a fundamental process for energy production within cells. Fatty acids, including hexadecenoic acid which forms hexadecenoylcarnitine, are transported into the mitochondria via the carnitine shuttle system, where they are converted into their acylcarnitine forms by carnitine palmitoyltransferases. Once inside the mitochondrial matrix, these acylcarnitines serve as indirect substrates for beta-oxidation, a catabolic process that systematically shortens fatty acid chains to generate acetyl-CoA for the citric acid cycle and subsequent ATP synthesis.[1] This process is initiated by a series of acyl-Coenzyme A dehydrogenases, such as short-chain acyl-Coenzyme A dehydrogenase (SCAD) and medium-chain acyl-Coenzyme A dehydrogenase (MCAD), each demonstrating a preference for specific fatty acid chain lengths, thereby controlling the metabolic flux through this essential energy pathway. [1]
Genetic and Transcriptional Regulation of Lipid Metabolism
Section titled “Genetic and Transcriptional Regulation of Lipid Metabolism”Metabolic regulation of acylcarnitine levels, including hexadecenoylcarnitine, is significantly influenced by genetic factors affecting enzyme activity and overall lipid homeostasis. Common genetic variants, such as intronic single nucleotide polymorphisms (SNPs) likers2014355 in SCAD and rs11161510 in MCAD, have been associated with altered ratios of specific acylcarnitines, indicating changes in enzymatic turnover. [1] For instance, minor allele homozygotes for these SNPs demonstrate reduced dehydrogenase activity, leading to higher concentrations of longer-chain fatty acid substrates and lower concentrations of shorter-chain products, thus modulating metabolic flux. [1]Furthermore, broader transcriptional regulation mechanisms, involving transcription factors such as SREBP-2, play a role in regulating the synthesis of cholesterol and fatty acids, indirectly influencing the substrate pool available for carnitine-mediated transport and subsequent beta-oxidation.[5]
Systems-Level Integration in Energy Homeostasis
Section titled “Systems-Level Integration in Energy Homeostasis”The pathways involving hexadecenoylcarnitine and other acylcarnitines are integral to systems-level energy homeostasis, exhibiting extensive crosstalk and network interactions within cellular metabolism. The efficient transport and oxidation of fatty acids are critical for maintaining the energy balance, especially during periods of high energy demand or fasting. This integration ensures that diverse lipid species are appropriately channeled towards either energy generation or biosynthesis, adapting to physiological needs.[1]The resulting metabolic profiles, or “metabotypes,” reflect the complex interplay of these pathways and their hierarchical regulation, demonstrating emergent properties that define an individual’s overall metabolic state and interact with environmental factors like nutrition and lifestyle.[1]
Dysregulation and Disease Susceptibility
Section titled “Dysregulation and Disease Susceptibility”Dysregulation within acylcarnitine metabolism, often originating from genetic variations or environmental influences, can lead to altered metabolic profiles with significant disease relevance. Imbalances in fatty acid oxidation, as indicated by perturbed acylcarnitine levels, contribute to the development of specific “metabotypes” that may increase an individual’s susceptibility to common multi-factorial diseases.[1]For example, disruptions in these pathways can contribute to dyslipidemia, a condition characterized by abnormal concentrations of plasma lipids, including LDL-cholesterol, HDL-cholesterol, and triglycerides, which are well-established risk factors for coronary artery disease.[5] The genetic influences on enzymes like HMGCR, which impacts LDL-cholesterol levels, further illustrate how specific genetic predispositions contribute to metabolic dysregulation and disease risk.[3]
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.
[2] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 12, 2008, pp. 1413-1418.
[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, vol. 28, no. 12, 2008, pp. 2071-2079.
[4] Melzer, D., et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genetics, vol. 4, no. 5, 2008, e1000072.
[5] 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.
[6] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 11, 2008, pp. 1293-1301.
[7] Koishi, R, et al. “Angptl3 regulates lipid metabolism in mice.” Nat Genet, vol. 30, no. 2, 2002, pp. 151-157.
[8] Romeo, S, et al. “Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.” Nat Genet, vol. 39, no. 4, 2007, pp. 513-516.
[9] Kuivenhoven, JA, et al. “The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.” J Lipid Res, vol. 38, no. 2, 1997, pp. 191-205.
[10] Hayhurst, GP, et al. “Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.” Mol Cell Biol, vol. 21, no. 4, 2001, pp. 1393-1403.
[11] Murphy, C, 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.
[12] Odom, DT, et al. “Control of pancreas and liver gene expression by HNF transcription factors.” Science, vol. 303, no. 5662, 2004, pp. 1378-1381.
[13] Shih, DQ, et al. “Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism.” Nat Genet, vol. 27, no. 4, 2001, pp. 375-382.
[14] Samani, NJ, et al. “Genomewide association analysis of coronary artery disease.”N Engl J Med, vol. 357, no. 5, 2007, pp. 443-453.