Acyl Coa Binding Domain Containing Protein 7
The ACBD7 (Acyl-CoA Binding Domain Containing Protein 7) gene provides instructions for making a protein involved in cellular metabolism, particularly the handling of lipids. Understanding the role of ACBD7 is crucial for unraveling complex metabolic pathways and their implications for human health.
Biological Basis
Section titled “Biological Basis”The protein encoded by ACBD7 belongs to the family of acyl-CoA binding proteins (ACBPs). These proteins are known to bind acyl-CoA esters, which are essential intermediates in numerous metabolic processes. Acyl-CoAs are involved in fatty acid synthesis and breakdown, lipid modification of proteins, and energy production. By binding and transporting these molecules, ACBD7 likely plays a role in regulating the availability and channeling of acyl-CoAs within the cell, thereby influencing overall lipid homeostasis. Research has linked genetic variations near ACBD7 to differences in the levels of specific lipids in human serum, such as plasmalogen/plasmenogen phosphatidylcholines (e.g., PC ae C33:1), indicating its involvement in lipid metabolism. [1]
Clinical Relevance
Section titled “Clinical Relevance”Variations in the ACBD7 gene and its protein product can impact an individual’s metabolic profile. The observed associations with specific lipid levels suggest that ACBD7may contribute to an individual’s risk for metabolic disorders, including those related to lipid dysregulation. Understanding these genetic influences can provide insights into the underlying mechanisms of conditions like cardiovascular disease, type 2 diabetes, and other metabolic syndromes where lipid metabolism plays a critical role. Further research intoACBD7 could lead to the identification of biomarkers or therapeutic targets for these conditions.
Social Importance
Section titled “Social Importance”The study of genes like ACBD7contributes significantly to the field of personalized medicine and public health. By identifying genetic factors that influence metabolite levels, researchers can better understand individual predispositions to certain health outcomes. This knowledge can potentially inform tailored dietary recommendations, lifestyle interventions, or targeted pharmaceutical strategies to maintain metabolic health. Furthermore, insights gained fromACBD7 research can enhance our fundamental understanding of human metabolism, paving the way for improved diagnostic tools and preventive measures for a range of chronic diseases.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The current understanding of genetic associations for traits potentially involving ACBD7 is shaped by the design and statistical power of the genome-wide association studies (GWAS) conducted. Many studies rely on meta-analyses of multiple cohorts, which, while increasing power, can introduce heterogeneity in study-specific genotyping quality control and analytical approaches . The interplay of these variants across different genes can contribute to an individual’s predisposition to various metabolic traits and conditions. For instance, variants can affect gene expression levels or alter the structure and activity of proteins, thereby impacting their roles in processes like fatty acid transport, inflammation, and cellular stress responses. [2]
The variant rs72774385 is associated with the ACBD7 gene, which encodes acyl-CoA binding domain containing protein 7. This protein is part of a family known for binding medium- and long-chain acyl-CoA esters, molecules crucial for fatty acid metabolism and energy production. While the precise functional impact of rs72774385 on ACBD7 activity requires further investigation, variants in acyl-CoA binding proteins can influence cellular lipid homeostasis, affecting the availability of fatty acids for synthesis, breakdown, or signaling. [2] Such alterations in acyl-CoA pools could have downstream effects on membrane composition, protein acylation, and overall metabolic health, potentially contributing to conditions like dyslipidemia or metabolic syndrome. [2]
Another significant variant, rs10418046 , is located in a genomic region containing NLRP12 and MYADM-AS1. NLRP12 (NLR family pyrin domain containing 12) is a key component of the inflammasome, a multiprotein complex that initiates inflammatory responses, playing a critical role in innate immunity and inflammation. [2] MYADM-AS1 is a long non-coding RNA (lncRNA) that may regulate gene expression in an antisense manner, potentially influencing the adjacent MYADM gene and broader cellular functions. Variations in this region, such as rs10418046 , could modulate inflammatory pathways or immune cell function, which are intricately linked to metabolic health and lipid handling, thereby indirectly affecting processes related to acyl-CoA metabolism. [2]
The rs3917549 variant is found within the PON1 gene, which codes for paraoxonase 1. PON1is primarily associated with high-density lipoprotein (HDL) and plays a vital role in protecting against oxidative stress by hydrolyzing oxidized lipids, particularly those in low-density lipoprotein (LDL).[2] Genetic variants in PON1can alter its enzymatic activity or expression levels, thereby influencing an individual’s susceptibility to oxidative damage and cardiovascular disease. GivenACBD7’s role in lipid metabolism, variations in PON1 activity could impact the overall oxidative state and inflammatory burden within lipid-rich environments, affecting the stability and function of acyl-CoA esters and related metabolic pathways. [2]
Lastly, the rs4693545 variant is associated with the COPS4 gene, which encodes a subunit of the COP9 signalosome complex. The COP9 signalosome is a highly conserved protein complex involved in regulating various cellular processes, including protein degradation, cell cycle progression, and signal transduction, primarily through its isopeptidase activity on ubiquitin-like proteins. [2] Variants like rs4693545 could potentially alter the function or stability of the COPS4 protein, leading to downstream effects on proteasomal activity and cellular regulatory networks. Such broad cellular impacts could indirectly influence metabolic pathways, including those involving acyl-CoA metabolism and lipid droplet formation, by affecting the degradation of key metabolic enzymes or regulatory proteins. [2]
Biological Background
Section titled “Biological Background”Lipid Metabolism and Fatty Acid Homeostasis
Section titled “Lipid Metabolism and Fatty Acid Homeostasis”Acyl coa binding domain containing protein 7 (ACBD7) is named for its association with acyl-CoA, a central molecule in cellular lipid metabolism. The human body synthesizes un- and monosaturated fatty acids up to 18 carbons long, such as palmitic acid (C16:0), stearic acid (C18:0), and oleic acid (C18:1).[1]Essential polyunsaturated fatty acids like linoleic acid (C18:2) and alpha-linolenic acid (C18:3) are obtained from the diet and serve as precursors for longer-chain polyunsaturated fatty acids (PUFAs) through specific metabolic pathways.[1] These fatty acids, often in their acyl-CoA form, are critical building blocks for various complex lipids.
The Kennedy pathway exemplifies how fatty acid moieties are incorporated into glycerophospholipids, such as phosphatidylcholines (PC). [1]This pathway involves linking two fatty acid moieties to glycerol 3-phosphate, followed by dephosphorylation and the addition of a phosphocholine moiety. Enzymes like fatty acid delta-5 desaturase (FADS1) play a crucial role in modifying the unsaturation of fatty acids, for instance, converting eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4), thereby influencing the composition of various glycerophospholipids. [1] Such processes highlight the dynamic nature of fatty acid remodeling and its impact on cellular lipid profiles.
Genetic Regulation of Lipid Pathways
Section titled “Genetic Regulation of Lipid Pathways”Genetic variations significantly influence lipid metabolism and the resulting lipid profiles. Polymorphisms in genes like FADS1 can affect the efficiency of key enzymatic reactions, such as the delta-5 desaturase reaction. [1] A minor allele variant of FADS1 (e.g., rs174548 ) has been associated with reduced delta-5 desaturase efficiency, leading to lower concentrations of phosphatidylcholines with four or more double bonds (e.g., PC aa C36:4) and increased concentrations of those with fewer double bonds (e.g., PC aa C36:3). [1] This demonstrates how genetic predispositions can alter the availability of specific fatty acid substrates for complex lipid synthesis.
Beyond fatty acid desaturation, other genes also play a substantial role in regulating lipid levels. For example, the HMGCRgene encodes 3-hydroxy-3-methylglutaryl-CoA reductase, a rate-limiting enzyme in cholesterol synthesis, and common single nucleotide polymorphisms (SNPs) in this gene are associated with LDL-cholesterol levels.[3] Similarly, variations in the APOC3gene, which encodes apolipoprotein CIII, are linked to hypertriglyceridemia and influence very low-density lipoprotein catabolism.[4] These genetic insights underscore the polygenic nature of lipid regulation and its susceptibility to inherited variations.
Biomolecular Interactions and Cellular Functions
Section titled “Biomolecular Interactions and Cellular Functions”The intricate balance of lipid metabolism involves numerous biomolecules and their cellular interactions. Glycerophospholipids, including diacyl phosphatidylcholines (PC aa), acyl-alkyl phosphatidylcholines (PC ae), phosphatidylethanolamines (PE aa), and phosphatidylinositol (PI aa), are fundamental components of cell membranes and signaling pathways. [1] The precise composition of their fatty acid side chains (e.g., C36:4 or C34:2) is crucial for their function and is influenced by enzymatic activities such as desaturation. [1]
Cellular lipid homeostasis also involves interconversions between different lipid classes. For instance, sphingomyelin can be synthesized from phosphatidylcholine through the action of sphingomyelin synthase, indicating a dynamic equilibrium among various lipid pools.[1]Furthermore, the regulation of lipoprotein metabolism involves critical proteins like lipoprotein lipase, which is responsible for the hydrolysis of triglycerides in circulating lipoproteins, and its activity can be inhibited by factors such as Angiopoietin-like protein 4.[5] These molecular interactions ensure the proper synthesis, modification, and catabolism of lipids within the cell and throughout the body.
Systemic Impact and Pathophysiological Relevance
Section titled “Systemic Impact and Pathophysiological Relevance”Disruptions in lipid metabolism can have profound systemic consequences, contributing to various pathophysiological conditions. Dyslipidemia, characterized by abnormal levels of plasma lipids such as high LDL-cholesterol and triglycerides, is a significant risk factor for cardiovascular diseases.[6] Genome-wide association studies have identified numerous genetic loci that contribute to the polygenic nature of dyslipidemia, highlighting the complex interplay of genetic and environmental factors. [6]
Altered lipid profiles are also implicated in metabolic disorders beyond cardiovascular disease. Variations in genes affecting triglyceride levels have been associated with an increased risk of type 2 diabetes.[7] Homeostatic disruptions, such as those resulting from reduced FADS1efficiency, can lead to imbalanced ratios of specific glycerophospholipids, reflecting a broader shift in polyunsaturated fatty acid metabolism.[1]These systemic changes in lipid composition and regulation underscore the importance of maintaining proper lipid homeostasis for overall health and disease prevention.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”The ‘acyl coa binding domain containing protein 7’ is implicated by its name in the intricate processes involving acyl-CoAs, which are central intermediates in various lipid metabolic pathways. While specific direct mechanisms for ACBD7are not detailed in the provided studies, the broader context of lipid metabolism, its regulation, and its dysregulation in disease states highlights the critical environment in which such a protein would function. The following sections describe the key pathways and regulatory networks relevant to lipid homeostasis as elucidated in the research, providing insight into the functional landscape where an acyl-CoA binding protein would exert its influence.
Metabolic Pathways of Lipid Synthesis and Catabolism
Section titled “Metabolic Pathways of Lipid Synthesis and Catabolism”Lipid metabolism involves complex pathways for the synthesis, modification, and breakdown of fatty acids, cholesterol, and phospholipids, all of which utilize acyl-CoA intermediates. De novo synthesis pathways produce un- and monosaturated fatty acids up to 18 carbons, such as palmitic, stearic, and oleic acids, while essential polyunsaturated fatty acids like linoleic and alpha-linolenic acids are processed through omega-6 and omega-3 synthesis pathways, respectively. [1] Fatty acid synthesis also involves enzymes like acyl-malonyl acyl carrier protein-condensing enzyme. [8] Cholesterol biosynthesis is critically regulated by HMG-CoA reductase within the mevalonate pathway, where its catalytic portion’s crystal structure provides insights into activity regulation. [9]
Triglyceride homeostasis is influenced by factors such as angiopoietin-like protein 4 (ANGPTL4), which acts as a potent inhibitor of lipoprotein lipase (LPL) and can induce hyperlipidemia. [5] Apolipoproteins like APOCIII are also crucial, with transgenic mice overexpressing APOCIIIexhibiting hypertriglyceridemia due to a diminished very low-density lipoprotein (VLDL) fractional catabolic rate.[4]Furthermore, the Kennedy pathway is central to phosphatidylcholine synthesis, where two fatty acid moieties are linked to glycerol 3-phosphate, followed by dephosphorylation and the addition of a phosphocholine moiety.[1] Enzymes such as FADS1 catalyze key desaturation steps, converting eicosatrienoyl-CoA (C20:3) to arachidonyl-CoA (C20:4) for the formation of specific glycerol-phosphatidylcholins. [1]
Regulatory Mechanisms in Lipid Homeostasis
Section titled “Regulatory Mechanisms in Lipid Homeostasis”The precise control of lipid metabolism involves multiple layers of regulation, including gene expression, post-translational protein modifications, and allosteric control. Gene regulation frequently involves alternative splicing of pre-mRNA, a mechanism that generates protein diversity and is implicated in human disease.[10]For instance, common single nucleotide polymorphisms (SNPs) inHMGCR can affect the alternative splicing of exon 13, influencing LDL-cholesterol levels. [3] Similarly, alternative splicing of APOB mRNA can be induced by antisense oligonucleotides, leading to novel APOB isoforms. [11]
Beyond transcriptional control, protein activity and stability are fine-tuned through mechanisms such as protein modification and degradation. The oligomerization state of HMG-CoA reductase, for example, influences its degradation rate, providing a post-translational regulatory checkpoint for cholesterol synthesis. [12] Hormonal signaling also plays a significant role, with genes like adiponutrinbeing regulated by insulin and glucose in human adipose tissue, affecting its expression and association with obesity.[13]The thyroid hormone receptor also engages in specific interactions with proteins that are either dependent on or inhibited by the presence of thyroid hormone, highlighting another layer of metabolic regulation.[14]
Signaling Networks and Inter-Pathway Crosstalk
Section titled “Signaling Networks and Inter-Pathway Crosstalk”Lipid metabolic pathways are not isolated but are integrated into complex signaling networks that involve receptor activation, intracellular cascades, and extensive crosstalk between different metabolic routes. Receptor-mediated interactions are crucial for lipid uptake and signaling, as exemplified by the low-density lipoprotein receptor-related protein (LRP) interacting with MafB, a regulator of hindbrain development. [15] Another example is Tim4, identified as a phosphatidylserine receptor, which could be involved in lipid recognition and cellular processes. [16]
Intracellular signaling cascades, such as those involving AMP-activated protein kinase (AMPK), play a role in energy sensing and metabolic regulation; for instance, the PRKAG2 gene encodes a heart-abundant gamma2 subunit of AMPK. [17]The mitogen-activated protein kinase (MAPK) pathway is also activated in various tissues, including skeletal muscle, influencing cellular responses that can impact metabolism.[18] These signaling events facilitate complex pathway crosstalk, where changes in one lipid pathway can influence others, contributing to the emergent properties of overall metabolic homeostasis. Genome-wide association network analysis (GWANA) further explores these interactions by integrating genetic associations with biological pathway information from Gene Ontology to identify enriched pathways. [19]
Dysregulation in Cardiometabolic Diseases
Section titled “Dysregulation in Cardiometabolic Diseases”Dysregulation of these intricate lipid metabolic and regulatory pathways is a fundamental mechanism underlying a spectrum of cardiometabolic diseases. Common genetic variants at multiple loci contribute to polygenic dyslipidemia, influencing plasma levels of various lipids. [2] For instance, variants in genes like APOA5, APOCIII, and LPL are consistently associated with lipid levels. [2] The GCKRgene, encoding glucokinase regulator, is associated with triglyceride levels and liver enzymes, indicating its role in metabolic health.[20]
Hypertriglyceridemia, a key feature of dyslipidemia, can arise from factors such as increased ANGPTL4 activity or altered apolipoprotein profiles, as seen with APOCIII. [5]Beyond lipids, genes involved in glucose metabolism, such asTCF7L2, confer risk for Type 2 Diabetes, highlighting the interconnectedness of lipid and glucose homeostasis.[21]Ultimately, these pathway dysregulations, whether in lipid synthesis, catabolism, or their regulatory control, contribute to an increased risk of coronary artery disease, making the components of these pathways, including proteins involved in acyl-CoA handling, potential therapeutic targets.[22]
Clinical Relevance
Section titled “Clinical Relevance”Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs72774385 | ACBD7 | acyl-CoA-binding domain-containing protein 7 measurement |
| rs10418046 | NLRP12 - MYADM-AS1 | monocyte count prefoldin subunit 5 measurement proteasome activator complex subunit 1 amount protein deglycase DJ-1 measurement protein fam107a measurement |
| rs3917549 | PON1 | acyl-CoA-binding domain-containing protein 7 measurement ragulator complex protein LAMTOR3 measurement tensin-4 measurement B-cell antigen receptor complex-associated protein alpha chain measurement cGMP-dependent protein kinase 1, beta isozyme measurement |
| rs4693545 | COPS4 | erythrocyte volume acyl-CoA-binding domain-containing protein 7 measurement protein 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] Kathiresan S, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2008;40(12):1426-1435.
[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, 2008, pp. 2071–2077.
[4] Aalto-Setala, K., et al. “Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.”J. Clin. Invest., vol. 90, 1992, pp. 1889–1900.
[5] Yoshida, K., et al. “Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase.”J. Lipid Res., vol. 43, 2002, pp. 1770–1772.
[6] Kathiresan, Sekar, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nature Genetics, vol. 41, no. 5, 2009, pp. 565-571.
[7] Saxena, R., et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.”Science, vol. 316, no. 5829, 2007, pp. 1331–1336.
[8] Toomey, R. E., and S. J. Wakil. “Studies on the mechanism of fatty acid synthesis. XVI. Preparation and general properties of acyl-malonyl acyl carrier protein-condensing enzyme from Escherichia coli.” J. Biol. Chem., vol. 241, 1966, pp. 1159–1165.
[9] Goldstein, J. L., and M. S. Brown. “Regulation of the mevalonate pathway.” Nature, vol. 343, 1990, pp. 425–430.
[10] Matlin, A. J., et al. “Understanding alternative splicing: towards a cellular code.” Nat Rev Mol Cell Biol, vol. 6, 2005, pp. 386–398.
[11] Khoo, B., et al. “Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB.” BMC Mol Biol, vol. 8, 2007, p. 3.
[12] Cheng, H. H., et al. “Oligomerization state influences the degradation rate of 3-hydroxy-3-methylglutaryl-CoA reductase.” J Biol Chem, vol. 274, 1999, pp. 17171–17178.
[13] Moldes, M., et al. “Adiponutrin gene is regulated by insulin and glucose in human adipose tissue.”Eur. J. Endocrinol., vol. 155, 2006, pp. 225–233.
[14] Lee, J. W., et al. “Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor.”Mol. Endocrinol., vol. 9, 1995, pp. 243–254.
[15] Petersen, H. H., et al. “Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development.”FEBS Lett., vol. 565, 2004, pp. 23–27.
[16] Miyanishi, M., et al. “Identification of Tim4 as a phosphatidylserine receptor.” Nature, vol. 450, 2007, pp. 435–439.
[17] Lang, T., et al. “Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant gamma2 subunit of 5’-AMP-activated protein kinase, to human chromosome 7q36.” Genomics, vol. 70, 2000, pp. 258-263.
[18] Williamson, D., et al. “Mitogen-activated protein kinase (MAPK) pathway activation: effects of age and acute exercise on human skeletal muscle.”J Physiol, vol. 574, no. 2, 2006, pp. 491-502.
[19] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 1, 2008, pp. 36-44.
[20] 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.
[21] Grant, S. F., et al. “Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.” Nat Genet, vol. 38, no. 3, 2006, pp. 320-323.
[22] 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.