ACADL

Last updated
ACADL
Identifiers
Aliases ACADL , acyl-CoA dehydrogenase, long chain, ACAD4, LCAD, acyl-CoA dehydrogenase long chain
External IDs OMIM: 609576 MGI: 87866 HomoloGene: 37498 GeneCards: ACADL
Orthologs
SpeciesHumanMouse
Entrez

33

11363

Ensembl

ENSG00000115361

ENSMUSG00000026003

UniProt

P28330

P51174

RefSeq (mRNA)

NM_001608

NM_007381

RefSeq (protein)

NP_001599

NP_031407

Location (UCSC) Chr 2: 210.19 – 210.23 Mb Chr 1: 66.87 – 66.9 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene. [5]

Contents

ACADL is a gene that encodes LCAD - acyl-CoA dehydrogenase, long chain - which is a member of the acyl-CoA dehydrogenase family. The acyl-CoA dehydrogenase family is primarily responsible for beta-oxidation of fatty acids within the mitochondria. LCAD dysfunction is associated with lowered fatty acid oxidation capacity and decreased heat generation. As a result, LCAD deficiency has been correlated with increased cardiac hypertrophy, pulmonary disease, and overall insulin resistance. [5]

Structure

Acadl is a single-copy, nuclear encoded gene approximately 35 kb in size. The gene contains 11 coding exons ranging in size from 67 bp to 275 bp, interrupted by 10 introns ranging in size from 1.0 kb to 6.6 kb in size. The Acadl 5' regulatory region, like other members of the Acad family, lacks a TATA or CAAT box and is GC rich. This region does contain multiple, putative cis-acting DNA elements recognized by either SP1 or members of the steroid-thyroid family of nuclear receptors, which has been shown with other members of the ACAD gene family to be important in regulated expression. [6]

Function

The LCAD enzyme catalyzes most of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LCAD works on long-chain fatty acids, typically between C12 and C16-acylCoA. LCAD is essential for oxidizing unsaturated fatty acids such as oleic acid, but seems redundant in the oxidation of saturated fatty acids. [7]

Fatty acid oxidation has proven to spare glucose in fasting conditions, and is also required for amino acid metabolism, which is essential for the maintenance of adequate glucose production. [8] LCAD is regulated by a reversible acetylation mechanism by SIRT3, in which the active form of the enzyme is deacetylated, and hyperacetylation reduces the enzymatic activity. [9] Moreover, LCAD participates in fatty acid metabolism and PPAR signaling pathway. [10]

Animal studies

In mice, LCAD deficient mice have been shown to expend less energy, and are also subject to hypothermia, which can be explained by the fact that a reduced rate of fatty acid oxidation is correlated with a lowered capacity to generate heat. [11] Indeed, when LCAD mice are exposed to the cold, the expression of fatty acid oxidation genes was elevated in liver. [12]

As ACADL is a mitochondrial protein, and a member of the beta-oxidation family, there are many instances in which its deficiency is correlated with mitochondrial dysfunction and the diseases that manifest as a result. The ACADL gene has been correlated with protecting against diabetes. [13] In corroboration, primary defects in mitochondrial fatty acid oxidation capacity, as illustrated by LCAD knockout mice, can lead to diacylglycerol accumulation, otherwise known as steatosis, as well as PKCepsilon activation, and hepatic insulin resistance. [14] In animals with very long-chain acyl-CoA dehydrogenase deficiency, LCAD and MCAD work to compensate for the reduced fatty acid oxidation capacity; this compensation is modest, however, and the fatty acid oxidation levels do not return completely to wild type levels. [15] Additionally, LCAD has been shown to have no mechanism that compensates for its deficiency. [7]

In the heart, LCAD knockout mice rely more heavily on glucose oxidation, concurrently while there is a large need for replenishment of metabolic intermediates, or anaplerosis. During fasting, the increased glucose usage cannot maintain homeostasis in LCAD knockout mice. [16] LCAD knockout mice displayed a higher level of cardiac hypertrophy, as indicated by increased left ventricular wall thickness and an increased amount of metabolic cardiomyopathy. [17] The knockout mice also had increased triglyceride levels in the myocardium, which is a detrimental disease phenotype. [18] Carnitine supplementation did lower the triglyceride levels in these knockout mice, but did not have any effect on hypertrophy or cardiac performance. [19]

The ACADL gene has also been linked to pathophysiology of pulmonary disease. In humans, this protein was shown to be localized to the human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. Mice that were lacking LCAD (-/-) had dysfunctional or reduced amounts of pulmonary surfactant, which is required to prevent infection; the mice who did not have this protein also displayed a significantly reduced lung capacity in a variety of tests. [9]

Clinical significance

As LCAD deficiency has not yet been found in humans, it has also been postulated that LCAD confers a critical role in development of the blastocoele in human embryos. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Medium-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Medium-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid oxidation that impairs the body's ability to break down medium-chain fatty acids into acetyl-CoA. The disorder is characterized by hypoglycemia and sudden death without timely intervention, most often brought on by periods of fasting or vomiting.

In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters the citric acid cycle, generating NADH and FADH2, which are electron carriers used in the electron transport chain. It is named as such because the beta carbon of the fatty acid chain undergoes oxidation and is converted to a carbonyl group to start the cycle all over again. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.

<span class="mw-page-title-main">Inborn error of lipid metabolism</span> Medical condition

Numerous genetic disorders are caused by errors in fatty acid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.

<span class="mw-page-title-main">Mitochondrial trifunctional protein deficiency</span> Medical condition

Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.

<span class="mw-page-title-main">ACADVL</span> Protein-coding gene in the species Homo sapiens

Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) is an enzyme that in humans is encoded by the ACADVL gene.

<span class="mw-page-title-main">ACADM</span> Mammalian protein found in Homo sapiens

ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.

<span class="mw-page-title-main">Short-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.

Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) and C3 (β) of the acyl-CoA thioester substrate. Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.

<span class="mw-page-title-main">ACADS</span> Protein-coding gene in humans

Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene is associated with short-chain acyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">Mitochondrial trifunctional protein</span> Inner mitochondrial membrane protein

Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits:

<span class="mw-page-title-main">Acyl-CoA</span> Group of coenzymes that metabolize fatty acids

Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.

<span class="mw-page-title-main">HADHA</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">Carnitine palmitoyltransferase I</span> Protein-coding gene in the species Homo sapiens

Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. The product is often Palmitoylcarnitine, but other fatty acids may also be substrates. It is part of a family of enzymes called carnitine acyltransferases. This "preparation" allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria.

<span class="mw-page-title-main">HADHB</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.

<span class="mw-page-title-main">Electron-transferring-flavoprotein dehydrogenase</span> Protein family

Electron-transferring-flavoprotein dehydrogenase is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane. It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the ETFDH gene. Deficiency in ETF dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.

<span class="mw-page-title-main">ETFA</span> Protein-coding gene in humans

The human ETFA gene encodes the Electron-transfer-flavoprotein, alpha subunit, also known as ETF-α. Together with Electron-transfer-flavoprotein, beta subunit, encoded by the 'ETFB' gene, it forms the heterodimeric electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ETFB</span> Protein-coding gene in humans

The human ETFB gene encodes the Electron-transfer-flavoprotein, beta subunit, also known as ETF-β. Together with Electron-transfer-flavoprotein, alpha subunit, encoded by the 'ETFA' gene, it forms the heterodimeric Electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ACAD9</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene. Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9.

<span class="mw-page-title-main">Fatty-acid metabolism disorder</span> Medical condition

A broad classification for genetic disorders that result from an inability of the body to produce or utilize an enzyme or transport protein that is required to oxidize fatty acids. They are an inborn error of lipid metabolism, and when it affects the muscles also a metabolic myopathy.

<span class="mw-page-title-main">Pirinixic acid</span> Chemical compound

Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes. Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction. It was discovered as WY-14,643 in 1974.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115361 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026003 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: Acyl-CoA dehydrogenase, long chain".
  6. ↑ Kurtz DM, Tolwani RJ, Wood PA (May 1998). "Structural characterization of the mouse long-chain acyl-CoA dehydrogenase gene and 5' regulatory region". Mammalian Genome. 9 (5): 361–5. doi:10.1007/s003359900770. PMID   9545492. S2CID   7445071.
  7. 1 2 Chegary M, te Brinke H, Ruiter JP, Wijburg FA, Stoll MS, Minkler PE, van Weeghel M, Schulz H, Hoppel CL, Wanders RJ, Houten SM (Aug 2009). "Mitochondrial long chain fatty acid beta-oxidation in man and mouse". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1791 (8): 806–15. doi:10.1016/j.bbalip.2009.05.006. PMC   2763615 . PMID   19465148.
  8. ↑ Goetzman ES, Alcorn JF, Bharathi SS, Uppala R, McHugh KJ, Kosmider B, Chen R, Zuo YY, Beck ME, McKinney RW, Skilling H, Suhrie KR, Karunanidhi A, Yeasted R, Otsubo C, Ellis B, Tyurina YY, Kagan VE, Mallampalli RK, Vockley J (Apr 2014). "Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction". The Journal of Biological Chemistry. 289 (15): 10668–79. doi: 10.1074/jbc.M113.540260 . PMC   4036448 . PMID   24591516.
  9. 1 2 Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV, Alt FW, Kahn CR, Verdin E (Mar 2010). "SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation". Nature. 464 (7285): 121–5. Bibcode:2010Natur.464..121H. doi:10.1038/nature08778. PMC   2841477 . PMID   20203611.
  10. ↑ Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ (May 2021). "Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance". Journal of Physiology and Biochemistry. 77 (2): 249–260. doi:10.1007/s13105-021-00791-3. PMID   33730333. S2CID   232300877.
  11. ↑ Diekman EF, van Weeghel M, Wanders RJ, Visser G, Houten SM (Jul 2014). "Food withdrawal lowers energy expenditure and induces inactivity in long-chain fatty acid oxidation-deficient mouse models". FASEB Journal. 28 (7): 2891–900. doi: 10.1096/fj.14-250241 . PMID   24648546. S2CID   44809746.
  12. ↑ Goetzman ES, Tian L, Wood PA (Jan 2005). "Differential induction of genes in liver and brown adipose tissue regulated by peroxisome proliferator-activated receptor-alpha during fasting and cold exposure in acyl-CoA dehydrogenase-deficient mice". Molecular Genetics and Metabolism. 84 (1): 39–47. doi:10.1016/j.ymgme.2004.09.010. PMID   15639194.
  13. ↑ Hamilton-Williams EE, Cheung J, Rainbow DB, Hunter KM, Wicker LS, Sherman LA (Jan 2012). "Cellular mechanisms of restored β-cell tolerance mediated by protective alleles of Idd3 and Idd5". Diabetes. 61 (1): 166–74. doi:10.2337/db11-0790. PMC   3237671 . PMID   22106155.
  14. ↑ Zhang D, Liu ZX, Choi CS, Tian L, Kibbey R, Dong J, Cline GW, Wood PA, Shulman GI (Oct 2007). "Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance". Proceedings of the National Academy of Sciences of the United States of America. 104 (43): 17075–80. Bibcode:2007PNAS..10417075Z. doi: 10.1073/pnas.0707060104 . PMC   2040460 . PMID   17940018.
  15. ↑ Tucci S, Herebian D, Sturm M, Seibt A, Spiekerkoetter U (2012). "Tissue-specific strategies of the very-long chain acyl-CoA dehydrogenase-deficient (VLCAD-/-) mouse to compensate a defective fatty acid β-oxidation". PLOS ONE. 7 (9): e45429. Bibcode:2012PLoSO...745429T. doi: 10.1371/journal.pone.0045429 . PMC   3443214 . PMID   23024820.
  16. ↑ Bakermans AJ, Dodd MS, Nicolay K, Prompers JJ, Tyler DJ, Houten SM (Dec 2013). "Myocardial energy shortage and unmet anaplerotic needs in the fasted long-chain acyl-CoA dehydrogenase knockout mouse". Cardiovascular Research. 100 (3): 441–9. doi: 10.1093/cvr/cvt212 . PMID   24042017.
  17. ↑ Cox KB, Liu J, Tian L, Barnes S, Yang Q, Wood PA (Dec 2009). "Cardiac hypertrophy in mice with long-chain acyl-CoA dehydrogenase or very long-chain acyl-CoA dehydrogenase deficiency". Laboratory Investigation. 89 (12): 1348–54. doi:10.1038/labinvest.2009.86. PMC   2787798 . PMID   19736549.
  18. ↑ Bakermans AJ, Geraedts TR, van Weeghel M, Denis S, João Ferraz M, Aerts JM, Aten J, Nicolay K, Houten SM, Prompers JJ (Sep 2011). "Fasting-induced myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice is accompanied by impaired left ventricular function". Circulation: Cardiovascular Imaging. 4 (5): 558–65. doi:10.1161/CIRCIMAGING.111.963751. PMID   21737602. S2CID   11307451.
  19. ↑ Bakermans AJ, van Weeghel M, Denis S, Nicolay K, Prompers JJ, Houten SM (Nov 2013). "Carnitine supplementation attenuates myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice". Journal of Inherited Metabolic Disease. 36 (6): 973–81. doi:10.1007/s10545-013-9604-4. PMID   23563854. S2CID   24751151.
  20. ↑ Visel A, Thaller C, Eichele G (Jan 2004). "GenePaint.org: an atlas of gene expression patterns in the mouse embryo". Nucleic Acids Research. 32 (Database issue): D552–6. doi:10.1093/nar/gkh029. PMC   308763 . PMID   14681479.

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