ACADL

Acyl-CoA dehydrogenase, long chain
Identifiers
Symbols ACADL ; ACAD4; LCAD
External IDs OMIM: 609576 HomoloGene: 37498 GeneCards: ACADL Gene
EC number 1.3.8.8
Orthologs
Species Human Mouse
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:
66.83 – 66.86 Mb
PubMed search

Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.[1]

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.[1]

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.[2]

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.[3]

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.[4] 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.[5]

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.[6] Indeed, when LCAD mice are exposed to the cold, the expression of fatty acid oxidation genes was elevated in liver.[7]

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.[8] 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.[9] 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.[10] Additionally, LCAD has been shown to have no mechanism that compensates for its deficiency.[3]

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 analplerosis. During fasting, the increased glucose usage cannot maintain homeostasis in LCAD knockout mice.[11] LCAD knockout mice displayed a higher level of cardiac hypertrophy, as indicated by increased left ventricular wall thickness and an increased about of metabolic cardiomyopathy.[12] The knockout mice also had increased triglyceride levels in the myocardium, which is a detrimental disease phenotype.[13] Carnitine supplementation did lower the triglyceride levels in these knockout mice, but did not have any effect on hypertrophy or cardiac performance.[14]

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.[5]

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.[15]

References

  1. 1 2 "Entrez Gene: Acyl-CoA dehydrogenase, long chain".
  2. ↑ 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.
  3. 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 1791 (8): 806–15. doi:10.1016/j.bbalip.2009.05.006. PMC 2763615. PMID 19465148.
  4. ↑ 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.
  5. 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. doi:10.1038/nature08778. PMC 2841477. PMID 20203611.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. doi:10.1073/pnas.0707060104. PMC 2040460. PMID 17940018.
  10. ↑ 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. doi:10.1371/journal.pone.0045429. PMC 3443214. PMID 23024820.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.

See also

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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