CoChat
Sign Up
Cited by 156Cancer, Lipids, and MetabolismMetabolism and Genetic DisordersMetabolism, Diabetes, and Cancer

Mitochondrial CPT1A: Insights into structure, function, and basis for drug development

Open access
Liang, Kai·2023·Frontiers in Pharmacology
DOI 10.3389/fphar.2023.1160440PMC PMC10076611
Open this paper in CoChat — free accountOpen PDF

Abstract

Carnitine Palmitoyl-Transferase1A (CPT1A) is the rate-limiting enzyme in the fatty acid β-oxidation, and its deficiency or abnormal regulation can result in diseases like metabolic disorders and various cancers. Therefore, CPT1A is a desirable drug target for clinical therapy. The deep comprehension of human CPT1A is crucial for developing the therapeutic inhibitors like Etomoxir. CPT1A is an appealing druggable target for cancer therapies since it is essential for the survival, proliferation, and drug resistance of cancer cells. It will help to lower the risk of cancer recurrence and metastasis, reduce mortality, and offer prospective therapy options for clinical treatment if the effects of CPT1A on the lipid metabolism of cancer cells are inhibited. Targeted inhibition of CPT1A can be developed as an effective treatment strategy for cancers from a metabolic perspective. However, the pathogenic mechanism and recent progress of CPT1A in diseases have not been systematically summarized. Here we discuss the functions of CPT1A in health and diseases, and prospective therapies targeting CPT1A. This review summarizes the current knowledge of CPT1A, hoping to prompt further understanding of it, and provide foundation for CPT1A-targeting drug development.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fphar.2023.1160440

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 139 · Cited by 156

Research works printed but not linked: 127

  1. Agostini M. Melino G. Habeb B. Calandria J. M. Bazan N. G. (2022). Targeting lipid metabolism in cancer: Neuroblastoma. Cancer Metastasis Rev. 41, 255– 260. 10.1007/s10555-022-10040-8 35687185 PMC9363363 · DOI
  2. Akkaoui M. Cohen I. Esnous C. Lenoir V. Sournac M. Girard J. (2009). Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids. Biochem. J. 420, 429– 438. 10.1042/BJ20081932 19302064 · DOI
  3. Arina A. Gutiontov S. I. Weichselbaum R. R. (2020). Radiotherapy and immunotherapy for cancer: From "systemic" to "multisite. Clin. Cancer Res. 26, 2777– 2782. 10.1158/1078-0432.CCR-19-2034 32047000 PMC10759929 · DOI
  4. Ashrafian H. Horowitz J. D. Frenneaux M. P. (2007). Perhexiline. Cardiovasc Drug Rev. 25, 76– 97. 10.1111/j.1527-3466.2007.00006.x 17445089 · DOI
  5. Aslibekyan S. Do A. N. Xu H. Li S. Irvin M. R. Zhi D. (2017). CPT1A methylation is associated with plasma adiponectin. Nutr. Metab. Cardiovasc Dis. 27, 225– 233. 10.1016/j.numecd.2016.11.004 28139377 PMC5330786 · DOI
  6. Bellusci M. Quijada-Fraile P. Barrio-Carreras D. Martin-Hernandez E. Garcia-Silva M. Merinero B. (2017). Carnitine palmitoyltransferase 1A deficiency: Abnormal muscle biopsy findings in a child presenting with reye's syndrome. J. Inherit. Metab. Dis. 40, 751– 752. 10.1007/s10545-017-0041-7 28466427 · DOI
  7. Bennett M. J. Boriack R. L. Narayan S. Rutledge S. L. Raff M. L. (2004). Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. Mol. Genet. Metab. 82, 59– 63. 10.1016/j.ymgme.2004.02.004 15110323 · DOI
  8. Bergers G. Fendt S. M. (2021). The metabolism of cancer cells during metastasis. Nat. Rev. Cancer 21, 162– 180. 10.1038/s41568-020-00320-2 33462499 PMC8733955 · DOI
  9. Bluher M. (2019). Obesity: Global epidemiology and pathogenesis. Nat. Rev. Endocrinol. 15, 288– 298. 10.1038/s41574-019-0176-8 30814686 · DOI · Paper page
  10. Bonnefont J. P. Djouadi F. Prip-Buus C. Gobin S. Munnich A. Bastin J. (2004). Carnitine palmitoyltransferases 1 and 2: Biochemical, molecular and medical aspects. Mol. Asp. Med. 25, 495– 520. 10.1016/j.mam.2004.06.004 15363638 · DOI · Paper page
  11. Brady P. S. Brady L. J. (1986). Action in vivo and in vitro of 2-tetradecylglycidic acid, 2-tetradecylglycidyl-CoA and 2-tetradecylglycidylcarnitine on hepatic carnitine palmitoyltransferase. Biochem. J. 238, 801– 809. 10.1042/bj2380801 3800962 PMC1147207 · DOI
  12. Brown N. F. Mullur R. S. Subramanian I. Esser V. Bennett M. J. Saudubray J. M. (2001). Molecular characterization of L-CPT I deficiency in six patients: Insights into function of the native enzyme. J. Lipid Res. 42, 1134– 1142. 10.1016/s0022-2275(20)31604-7 11441142 · DOI
  13. Camarda R. Zhou A. Y. Kohnz R. A. Balakrishnan S. Mahieu C. Anderton B. (2016). Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat. Med. 22, 427– 432. 10.1038/nm.4055 26950360 PMC4892846 · DOI
  14. Carlsson S. Vickers A. J. Roobol M. Eastham J. Scardino P. Lilja H. (2012). Prostate cancer screening: Facts, statistics, and interpretation in response to the US preventive services task force review. J. Clin. Oncol. 30, 2581– 2584. 10.1200/JCO.2011.40.4327 22711853 PMC3413273 · DOI
  15. Ceccarelli S. M. Chomienne O. Gubler M. Arduini A. (2011). Carnitine palmitoyltransferase (CPT) modulators: A medicinal chemistry perspective on 35 years of research. J. Med. Chem. 54, 3109– 3152. 10.1021/jm100809g 21504156 · DOI
  16. Chatelain F. Kohl C. Esser V. McGarry J. D. Girard J. Pegorier J. P. (1996). Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes. Eur. J. Biochem. 235, 789– 798. 10.1111/j.1432-1033.1996.00789.x 8654430 · DOI · Paper page
  17. Chua M. L. K. Wee J. T. S. Hui E. P. Chan A. T. C. (2016). Nasopharyngeal carcinoma. Lancet 387, 1012– 1024. 10.1016/S0140-6736(15)00055-0 26321262 · DOI
  18. Collins S. A. Sinclair G. McIntosh S. Bamforth F. Thompson R. Sobol I. (2010). Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in yukon, northwest territories, and nunavut. Mol. Genet. Metab. 101, 200– 204. 10.1016/j.ymgme.2010.07.013 20696606 · DOI
  19. Corn K. C. Windham M. A. Rafat M. (2020). Lipids in the tumor microenvironment: From cancer progression to treatment. Prog. Lipid Res. 80, 101055. 10.1016/j.plipres.2020.101055 32791170 PMC7674189 · DOI
  20. Cox R. L. (2017). Rationally designed PPARδ-specific agonists and their therapeutic potential for metabolic syndrome. Proc. Natl. Acad. Sci. U. S. A. 114, 3284– 3285. 10.1073/pnas.1702084114 28320957 PMC5380081 · DOI
  21. Culp M. B. Soerjomataram I. Efstathiou J. A. Bray F. Jemal A. (2020). Recent global patterns in prostate cancer incidence and mortality rates. Eur. Urol. 77, 38– 52. 10.1016/j.eururo.2019.08.005 31493960 · DOI · Paper page
  22. Dai J. Zhu H. Shi J. Woldegiorgis G. (2000). Identification by mutagenesis of conserved arginine and tryptophan residues in rat liver carnitine palmitoyltransferase I important for catalytic activity. J. Biol. Chem. 275, 22020– 22024. 10.1074/jbc.M002118200 10801831 · DOI
  23. Darragh L. B. Oweida A. J. Karam S. D. (2018). Overcoming resistance to combination radiation-immunotherapy: A focus on contributing pathways within the tumor microenvironment. Front. Immunol. 9, 3154. 10.3389/fimmu.2018.03154 30766539 PMC6366147 · DOI
  24. de Sousa V. M. L. Carvalho L. (2018). Heterogeneity in lung cancer. Pathobiology 85, 96– 107. 10.1159/000487440 29635240 · DOI
  25. Deprince A. Haas J. T. Staels B. (2020). Dysregulated lipid metabolism links NAFLD to cardiovascular disease. Mol. Metab. 42, 101092. 10.1016/j.molmet.2020.101092 33010471 PMC7600388 · DOI
  26. Dheeraj A. Agarwal C. Schlaepfer I. R. Raben D. Singh R. Agarwal R. (2018). A novel approach to target hypoxic cancer cells via combining beta-oxidation inhibitor etomoxir with radiation. Hypoxia (Auckl) 6, 23– 33. 10.2147/HP.S163115 30175155 PMC6109663 · DOI
  27. Dowsett L. Lulis L. Ficicioglu C. Cuddapah S. (2017). Utility of genetic testing for confirmation of abnormal newborn screening in disorders of long-chain fatty acids: A missed case of carnitine palmitoyltransferase 1A (CPT1A) deficiency. Int. J. Neonatal Screen 3, 10. 10.3390/ijns3020010 28748224 PMC5523953 · DOI
  28. Drawz P. E. Rosenberg M. E. (2013). Slowing progression of chronic kidney disease. Kidney Int. Suppl. 3, 372– 376. 10.1038/kisup.2013.80 PMC4089661 25019022 · DOI
  29. Du Q. Tan Z. Shi F. Tang M. Xie L. Zhao L. (2019). PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation. Cancer Sci. 110, 2050– 2062. 10.1111/cas.14011 30945396 PMC6550130 · DOI
  30. El-Rifai W. Moskaluk C. A. Abdrabbo M. K. Harper J. Yoshida C. Riggins G. J. (2002). Gastric cancers overexpress S100A calcium-binding proteins. Cancer Res. 62, 6823– 6826. 12460893
  31. Fado R. Rodriguez-Rodriguez R. Casals N. (2021). The return of malonyl-CoA to the brain: Cognition and other stories. Prog. Lipid Res. 81, 101071. 10.1016/j.plipres.2020.101071 33186641 · DOI
  32. Falik-Borenstein Z. C. Jordan S. C. Saudubray J. M. Brivet M. Demaugre F. Edmond J. (1992). Brief report: Renal tubular acidosis in carnitine palmitoyltransferase type 1 deficiency. N. Engl. J. Med. 327, 24– 27. 10.1056/NEJM199207023270105 1598098 · DOI
  33. Fang P. Yu M. Shi M. Bo P. Gu X. Zhang Z. (2020). Baicalin and its aglycone: A novel approach for treatment of metabolic disorders. Pharmacol. Rep. 72, 13– 23. 10.1007/s43440-019-00024-x 32016847 · DOI
  34. Faye A. Esnous C. Price N. T. Onfray M. A. Girard J. Prip-Buus C. (2007). Rat liver carnitine palmitoyltransferase 1 forms an oligomeric complex within the outer mitochondrial membrane. J. Biol. Chem. 282, 26908– 26916. 10.1074/jbc.M705418200 17650509 · DOI
  35. Ferlay J. Colombet M. Soerjomataram I. Parkin D. M. Pineros M. Znaor A. (2021). Cancer statistics for the year 2020: An overview. Int. J. Cancer 149, 778– 789. 10.1002/ijc.33588 33818764 · DOI
  36. Fraser F. Corstorphine C. G. Zammit V. A. (1997). Topology of carnitine palmitoyltransferase I in the mitochondrial outer membrane. Biochem. J. 323 (3), 711– 718. 10.1042/bj3230711 9169604 PMC1218374 · DOI
  37. Gessner B. D. Gillingham M. B. Birch S. Wood T. Koeller D. M. (2010). Evidence for an association between infant mortality and a carnitine palmitoyltransferase 1A genetic variant. Pediatrics 126, 945– 951. 10.1542/peds.2010-0687 20937660 · DOI
  38. Giannessi F. Pessotto P. Tassoni E. Chiodi P. Conti R. De Angelis F. (2003). Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity. J. Med. Chem. 46, 303– 309. 10.1021/jm020979u 12519067 · DOI
  39. Gobin S. Bonnefont J. P. Prip-Buus C. Mugnier C. Ferrec M. Demaugre F. (2002). Organization of the human liver carnitine palmitoyltransferase 1 gene (CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia. Hum. Genet. 111, 179– 189. 10.1007/s00439-002-0752-0 12189492 · DOI
  40. Gobin S. Thuillier L. Jogl G. Faye A. Tong L. Chi M. (2003). Functional and structural basis of carnitine palmitoyltransferase 1A deficiency. J. Biol. Chem. 278, 50428– 50434. 10.1074/jbc.M310130200 14517221 · DOI
  41. Han S. Wei R. Zhang X. Jiang N. Fan M. Huang J. H. (2019). CPT1A/2-Mediated FAO enhancement-A metabolic target in radioresistant breast cancer. Front. Oncol. 9, 1201. 10.3389/fonc.2019.01201 31803610 PMC6873486 · DOI
  42. Hao F. Tian M. Zhang X. Jin X. Jiang Y. Sun X. (2021). Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation. Proc. Natl. Acad. Sci. U. S. A. 118, e2014681118. 10.1073/pnas.2014681118 34035164 PMC8179238 · DOI
  43. Heimberg M. Olubadewo J. O. Wilcox H. G. (1985). Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states. Endocr. Rev. 6, 590– 607. 10.1210/edrv-6-4-590 3908084 · DOI
  44. Holubarsch C. J. Rohrbach M. Karrasch M. Boehm E. Polonski L. Ponikowski P. (2007). A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: The ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. (Lond) 113, 205– 212. 10.1042/CS20060307 17319797 · DOI
  45. Houten S. M. Violante S. Ventura F. V. Wanders R. J. (2016). The biochemistry and physiology of mitochondrial fatty acid beta-oxidation and its genetic disorders. Annu. Rev. Physiol. 78, 23– 44. 10.1146/annurev-physiol-021115-105045 26474213 · DOI
  46. Hoy A. J. Nagarajan S. R. Butler L. M. (2021). Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat. Rev. Cancer 21, 753– 766. 10.1038/s41568-021-00388-4 34417571 · DOI
  47. Idrovo J. P. Yang W. L. Nicastro J. Coppa G. F. Wang P. (2012). Stimulation of carnitine palmitoyltransferase 1 improves renal function and attenuates tissue damage after ischemia/reperfusion. J. Surg. Res. 177, 157– 164. 10.1016/j.jss.2012.05.053 22698429 PMC3423512 · DOI
  48. Ijlst L. Mandel H. Oostheim W. Ruiter J. P. Gutman A. Wanders R. J. (1998). Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. J. Clin. Invest. 102, 527– 531. 10.1172/JCI2927 9691089 PMC508913 · DOI
  49. Iliopoulos D. Drosatos K. Hiyama Y. Goldberg I. J. Zannis V. I. (2010). MicroRNA-370 controls the expression of microRNA-122 and Cpt1alpha and affects lipid metabolism. J. Lipid Res. 51, 1513– 1523. 10.1194/jlr.M004812 20124555 PMC3035515 · DOI
  50. Indiveri C. Iacobazzi V. Tonazzi A. Giangregorio N. Infantino V. Convertini P. (2011). The mitochondrial carnitine/acylcarnitine carrier: Function, structure and physiopathology. Mol. Asp. Med. 32, 223– 233. 10.1016/j.mam.2011.10.008 22020112 · DOI
  51. Jackson-Hayes L. Song S. Lavrentyev E. N. Jansen M. S. Hillgartner F. B. Tian L. (2003). A thyroid hormone response unit formed between the promoter and first intron of the carnitine palmitoyltransferase-Ialpha gene mediates the liver-specific induction by thyroid hormone. J. Biol. Chem. 278, 7964– 7972. 10.1074/jbc.M211062200 12493735 · DOI
  52. Jenei Z. A. Borthwick K. Zammit V. A. Dixon A. M. (2009). Self-association of transmembrane domain 2 (TM2), but not TM1, in carnitine palmitoyltransferase 1A: Role of GXXXG(A) motifs. J. Biol. Chem. 284, 6988– 6997. 10.1074/jbc.M808487200 19136561 PMC2652319 · DOI
  53. Jiang N. Xie B. Xiao W. Fan M. Xu S. Duan Y. (2022). Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat. Commun. 13, 1511. 10.1038/s41467-022-29137-3 35314680 PMC8938495 · DOI
  54. Josefowicz S. Z. Lu L. F. Rudensky A. Y. (2012). Regulatory T cells: Mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531– 564. 10.1146/annurev.immunol.25.022106.141623 22224781 PMC6066374 · DOI · Paper page
  55. Joshi M. Stoykova G. E. Salzmann-Sullivan M. Dzieciatkowska M. Liebman L. N. Deep G. (2019). CPT1A supports castration-resistant prostate cancer in androgen-deprived conditions. Cells 8, 1115. 10.3390/cells8101115 31547059 PMC6830347 · DOI
  56. Kersten S. Seydoux J. Peters J. M. Gonzalez F. J. Desvergne B. Wahli W. (1999). Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489– 1498. 10.1172/JCI6223 10359558 PMC408372 · DOI · Paper page
  57. Khandrika L. Kumar B. Koul S. Maroni P. Koul H. K. (2009). Oxidative stress in prostate cancer. Cancer Lett. 282, 125– 136. 10.1016/j.canlet.2008.12.011 19185987 PMC2789743 · DOI
  58. Kim S. J. Park S. J. Park J. Cho H. J. Shim J. K. Seon J. (2022). Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres. J. Neurooncol 160, 677– 689. 10.1007/s11060-022-04189-z 36396930 · DOI
  59. Kurmi K. Hitosugi S. Wiese E. K. Boakye-Agyeman F. Gonsalves W. I. Lou Z. (2018). Carnitine palmitoyltransferase 1A has a lysine succinyltransferase activity. Cell Rep. 22, 1365– 1373. 10.1016/j.celrep.2018.01.030 29425493 PMC5826573 · DOI
  60. Le May C. Cauzac M. Diradourian C. Perdereau D. Girard J. Burnol A. F. (2005). Fatty acids induce L-CPT I gene expression through a PPARalpha-independent mechanism in rat hepatoma cells. J. Nutr. 135, 2313– 2319. 10.1093/jn/135.10.2313 16177188 · DOI
  61. Lee K. Kerner J. Hoppel C. L. (2011). Mitochondrial carnitine palmitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid transfer complex. J. Biol. Chem. 286, 25655– 25662. 10.1074/jbc.M111.228692 21622568 PMC3138250 · DOI · Paper page
  62. Li L. Wu L. Wang C. Liu L. Zhao Y. (2007). Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes. Regul. Pept. 139, 72– 79. 10.1016/j.regpep.2006.10.007 17109977 · DOI
  63. Lin C. W. Peng Y. J. Lin Y. Y. Mersmann H. J. Ding S. T. (2020). LRRK2 regulates CPT1A to promote beta-oxidation in HepG2 cells. Molecules 25, 4122. 10.3390/molecules25184122 32916992 PMC7570678 · DOI
  64. Lin H. Lu J. P. Laflamme P. Qiao S. Shayegan B. Bryskin I. (2010). Inter-related in vitro effects of androgens, fatty acids and oxidative stress in prostate cancer: A mechanistic model supporting prevention strategies. Int. J. Oncol. 37, 761– 766. 10.3892/ijo_00000725 20811696 · DOI
  65. Lopez-Vinas E. Bentebibel A. Gurunathan C. Morillas M. de Arriaga D. Serra D. (2007). Definition by functional and structural analysis of two malonyl-CoA sites in carnitine palmitoyltransferase 1A. J. Biol. Chem. 282, 18212– 18224. 10.1074/jbc.M700885200 17452323 · DOI
  66. Lu W. Che X. Qu X. Zheng C. Yang X. Bao B. (2021). Succinylation regulators promote clear cell renal cell carcinoma by immune regulation and RNA N6-methyladenosine methylation. Front. Cell Dev. Biol. 9, 622198. 10.3389/fcell.2021.622198 33681201 PMC7935513 · DOI
  67. Luo M. Liu Y. Q. Zhang H. Luo C. H. Liu Q. Wang W. Y. (2022). Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells. Lab. Invest. 102, 722– 730. 10.1038/s41374-021-00724-0 34963686 · DOI
  68. Mao L. Peng L. Ren X. Chu Y. Nie T. Lin W. (2022). Discovery of JND003 as a new selective estrogen-related receptor alpha agonist alleviating nonalcoholic fatty liver disease and insulin resistance. ACS Bio Med. Chem. Au 2, 282– 296. 10.1021/acsbiomedchemau.1c00050 PMC9302452 35874496 · DOI
  69. Mao S. Ling Q. Pan J. Li F. Huang S. Ye W. (2021). Inhibition of CPT1a as a prognostic marker can synergistically enhance the antileukemic activity of ABT199. J. Transl. Med. 19, 181. 10.1186/s12967-021-02848-9 33926484 PMC8082622 · DOI
  70. McGarry J. D. Leatherman G. F. Foster D. W. (1978). Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J. Biol. Chem. 253, 4128– 4136. 10.1016/s0021-9258(17)34693-8 659409 · DOI
  71. Mera P. Bentebibel A. Lopez-Vinas E. Cordente A. G. Gurunathan C. Sebastian D. (2009). C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochem. Pharmacol. 77, 1084– 1095. 10.1016/j.bcp.2008.11.020 19094968 · DOI · Paper page
  72. Michalek R. D. Gerriets V. A. Nichols A. G. Inoue M. Kazmin D. Chang C. Y. (2011). Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc. Natl. Acad. Sci. U. S. A. 108, 18348– 18353. 10.1073/pnas.1108856108 22042850 PMC3215012 · DOI · Paper page
  73. Miguel V. Tituana J. Herrero J. I. Herrero L. Serra D. Cuevas P. (2021). Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. J. Clin. Invest. 131, e140695. 10.1172/JCI140695 33465052 PMC7919728 · DOI
  74. Morillas M. Lopez-Vinas E. Valencia A. Serra D. Gomez-Puertas P. Hegardt F. G. (2004). Structural model of carnitine palmitoyltransferase I based on the carnitine acetyltransferase crystal. Biochem. J. 379, 777– 784. 10.1042/BJ20031373 14711372 PMC1224103 · DOI
  75. Morkholt A. S. Trabjerg M. S. Oklinski M. K. E. Bolther L. Kroese L. J. Pritchard C. E. J. (2019). CPT1A plays a key role in the development and treatment of multiple sclerosis and experimental autoimmune encephalomyelitis. Sci. Rep. 9, 13299. 10.1038/s41598-019-49868-6 31527712 PMC6746708 · DOI
  76. Munir R. Lisec J. Swinnen J. V. Zaidi N. (2019). Lipid metabolism in cancer cells under metabolic stress. Br. J. Cancer 120, 1090– 1098. 10.1038/s41416-019-0451-4 31092908 PMC6738079 · DOI
  77. Mynatt R. L. Park E. A. Thorngate F. E. Das H. K. Cook G. A. (1994). Changes in carnitine palmitoyltransferase-I mRNA abundance produced by hyperthyroidism and hypothyroidism parallel changes in activity. Biochem. Biophys. Res. Commun. 201, 932– 937. 10.1006/bbrc.1994.1791 8003033 · DOI
  78. Nakamura M. T. Yudell B. E. Loor J. J. (2014). Regulation of energy metabolism by long-chain fatty acids. Prog. Lipid Res. 53, 124– 144. 10.1016/j.plipres.2013.12.001 24362249 · DOI
  79. O'Byrne K. J. Barr M. P. Gray S. G. (2011). The role of epigenetics in resistance to Cisplatin chemotherapy in lung cancer. Cancers (Basel) 3, 1426– 1453. 10.3390/cancers3011426 24212667 PMC3756421 · DOI
  80. Ogawa E. Kanazawa M. Yamamoto S. Ohtsuka S. Ogawa A. Ohtake A. (2002). Expression analysis of two mutations in carnitine palmitoyltransferase IA deficiency. J. Hum. Genet. 47, 342– 347. 10.1007/s100380200047 12111367 · DOI
  81. Ostrom Q. T. Patil N. Cioffi G. Waite K. Kruchko C. Barnholtz-Sloan J. S. (2020). CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro Oncol. 22, iv1– iv96. 10.1093/neuonc/noaa200 33123732 PMC7596247 · DOI
  82. Park E. A. Mynatt R. L. Cook G. A. Kashfi K. (1995). Insulin regulates enzyme activity, malonyl-CoA sensitivity and mRNA abundance of hepatic carnitine palmitoyltransferase-I. Biochem. J. 310 (3), 853– 858. 10.1042/bj3100853 7575418 PMC1135974 · DOI
  83. Park J. H. Vithayathil S. Kumar S. Sung P. L. Dobrolecki L. E. Putluri V. (2016). Fatty acid oxidation-driven src links mitochondrial energy reprogramming and oncogenic properties in triple-negative breast cancer. Cell Rep. 14, 2154– 2165. 10.1016/j.celrep.2016.02.004 26923594 PMC4809061 · DOI
  84. Pearce O. M. T. Delaine-Smith R. M. Maniati E. Nichols S. Wang J. Bohm S. (2018). Deconstruction of a metastatic tumor microenvironment reveals a common matrix response in human cancers. Cancer Discov. 8, 304– 319. 10.1158/2159-8290.CD-17-0284 29196464 PMC5837004 · DOI
  85. Prip-Buus C. Thuillier L. Abadi N. Prasad C. Dilling L. Klasing J. (2001). Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community. Mol. Genet. Metab. 73, 46– 54. 10.1006/mgme.2001.3176 11350182 · DOI
  86. Rajakumar C. Ban M. R. Cao H. Young T. K. Bjerregaard P. Hegele R. A. (2009). Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I. J. Lipid Res. 50, 1223– 1228. 10.1194/jlr.P900001-JLR200 19181627 PMC2681405 · DOI
  87. Ramsay R. R. Gandour R. D. van der Leij F. R. (2001). Molecular enzymology of carnitine transfer and transport. Biochim. Biophys. Acta 1546, 21– 43. 10.1016/s0167-4838(01)00147-9 11257506 · DOI
  88. Rao J. N. Warren G. Z. L. Estolt-Povedano S. Zammit V. A. Ulmer T. S. (2011). An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A. J. Biol. Chem. 286, 42545– 42554. 10.1074/jbc.M111.306951 21990363 PMC3234983 · DOI
  89. Ratheiser K. Schneeweiss B. Waldhausl W. Fasching P. Korn A. Nowotny P. (1991). Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus. Metabolism 40, 1185– 1190. 10.1016/0026-0495(91)90214-h 1943747 · DOI
  90. Ren Z. Chen S. Seo J. E. Guo X. Li D. Ning B. (2020). Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline. Toxicol Vitro 69, 104987. 10.1016/j.tiv.2020.104987 PMC7938330 32861758 · DOI
  91. Rinaldi C. Schmidt T. Situ A. J. Johnson J. O. Lee P. R. Chen K. L. (2015). Mutation in CPT1C associated with pure autosomal dominant spastic paraplegia. JAMA Neurol. 72, 561– 570. 10.1001/jamaneurol.2014.4769 25751282 PMC5612424 · DOI
  92. Robert X. Gouet P. (2014). Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 42, W320– W324. 10.1093/nar/gku316 24753421 PMC4086106 · DOI · Paper page
  93. Robinson I. N. Zammit V. A. (1982). Sensitivity of carnitine acyltransferase I to malonly-CoA inhibition in isolated rat liver mitochondria is quantitatively related to hepatic malonyl-CoA concentration in vivo. Biochem. J. 206, 177– 179. 10.1042/bj2060177 7126192 PMC1158567 · DOI
  94. Rohlenova K. Veys K. Miranda-Santos I. De Bock K. Carmeliet P. (2018). Endothelial cell metabolism in health and disease. Trends Cell Biol. 28, 224– 236. 10.1016/j.tcb.2017.10.010 29153487 · DOI
  95. Rufer A. C. Thoma R. Hennig M. (2009). Structural insight into function and regulation of carnitine palmitoyltransferase. Cell Mol. Life Sci. 66, 2489– 2501. 10.1007/s00018-009-0035-1 19430727 PMC11115844 · DOI
  96. Savage P. A. Malchow S. Leventhal D. S. (2013). Basic principles of tumor-associated regulatory T cell biology. Trends Immunol. 34, 33– 40. 10.1016/j.it.2012.08.005 22999714 PMC3534814 · DOI
  97. Schlaepfer I. R. Joshi M. (2020). CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential. Endocrinology 161, bqz046. 10.1210/endocr/bqz046 31900483 · DOI
  98. Schlaepfer I. R. Rider L. Rodrigues L. U. Gijon M. A. Pac C. T. Romero L. (2014). Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol. Cancer Ther. 13, 2361– 2371. 10.1158/1535-7163.MCT-14-0183 25122071 PMC4185227 · DOI
  99. Selby P. L. Sherratt H. S. (1989). Substituted 2-oxiranecarboxylic acids: A new group of candidate hypoglycaemic drugs. Trends Pharmacol. Sci. 10, 495– 500. 10.1016/0165-6147(89)90049-7 2694542 · DOI
  100. Shao H. Mohamed E. M. Xu G. G. Waters M. Jing K. Ma Y. (2016). Carnitine palmitoyltransferase 1A functions to repress FoxO transcription factors to allow cell cycle progression in ovarian cancer. Oncotarget 7, 3832– 3846. 10.18632/oncotarget.6757 26716645 PMC4826173 · DOI
  101. Shepherd P. R. Kahn B. B. (1999). Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N. Engl. J. Med. 341, 248– 257. 10.1056/NEJM199907223410406 10413738 · DOI · Paper page
  102. Shi J. Fu H. Jia Z. He K. Fu L. Wang W. (2016). High expression of CPT1A predicts adverse outcomes: A potential therapeutic target for acute myeloid leukemia. EBioMedicine 14, 55– 64. 10.1016/j.ebiom.2016.11.025 27916548 PMC5161445 · DOI
  103. Singh B. K. Sinha R. A. Tripathi M. Mendoza A. Ohba K. Sy J. A. C. (2018). Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Sci. Signal 11, eaam5855. 10.1126/scisignal.aam5855 29945885 · DOI · Paper page
  104. Stoler J. M. Sabry M. A. Hanley C. Hoppel C. L. Shih V. E. (2004). Successful long-term treatment of hepatic carnitine palmitoyltransferase I deficiency and a novel mutation. J. Inherit. Metab. Dis. 27, 679– 684. 10.1023/b:boli.0000042979.42120.55 15669684 · DOI
  105. Sun W. Nie T. Li K. Wu W. Long Q. Feng T. (2021). Erratum. Hepatic CPT1A facilitates liver-adipose cross talk via induction of FGF21 in mice. Diabetes 2022;71:31-42. Diabetes 71, 1827. 10.2337/db22-er08a PMC9908405 35671193 · DOI
  106. Tamura K. Stecher G. Kumar S. (2021). MEGA11: Molecular evolutionary genetics analysis version 11. Mol. Biol. Evol. 38, 3022– 3027. 10.1093/molbev/msab120 33892491 PMC8233496 · DOI
  107. Tan Z. Xiao L. Tang M. Bai F. Li J. Li L. (2018). Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy. Theranostics 8, 2329– 2347. 10.7150/thno.21451 29721083 PMC5928893 · DOI
  108. Tan Z. Zou Y. Zhu M. Luo Z. Wu T. Zheng C. (2021). Carnitine palmitoyl transferase 1A is a novel diagnostic and predictive biomarker for breast cancer. BMC Cancer 21, 409. 10.1186/s12885-021-08134-7 33858374 PMC8048260 · DOI
  109. Tang M. Dong X. Xiao L. Tan Z. Luo X. Yang L. (2022). CPT1A-mediated fatty acid oxidation promotes cell proliferation via nucleoside metabolism in nasopharyngeal carcinoma. Cell Death Dis. 13, 331. 10.1038/s41419-022-04730-y 35411000 PMC9001659 · DOI
  110. Tomita K. Tamiya G. Ando S. Kitamura N. Koizumi H. Kato S. (2005). AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin. Exp. Res. 29, 240S– 245S. 10.1097/01.alc.0000191126.11479.69 16385230 · DOI
  111. Torre L. A. Bray F. Siegel R. L. Ferlay J. Lortet-Tieulent J. Jemal A. (2015). Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87– 108. 10.3322/caac.21262 25651787 · DOI
  112. Valentino A. Calarco A. Di Salle A. Finicelli M. Crispi S. Calogero R. A. (2017). Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: Molecular basis and pathophysiological consequences. Oncogene 36, 6030– 6040. 10.1038/onc.2017.216 28671672 · DOI
  113. Virmani A. Pinto L. Bauermann O. Zerelli S. Diedenhofen A. Binienda Z. K. (2015). The carnitine palmitoyl transferase (CPT) system and possible relevance for neuropsychiatric and neurological conditions. Mol. Neurobiol. 52, 826– 836. 10.1007/s12035-015-9238-7 26041663 · DOI · Paper page
  114. Waks A. G. Winer E. P. (2019). Breast cancer treatment: A review. JAMA 321, 288– 300. 10.1001/jama.2018.19323 30667505 · DOI
  115. Wang C. Zhang C. Li X. Shen J. Xu Y. Shi H. (2019). CPT1A-mediated succinylation of S100A10 increases human gastric cancer invasion. J. Cell Mol. Med. 23, 293– 305. 10.1111/jcmm.13920 30394687 PMC6307794 · DOI
  116. Wang D. Lippard S. J. (2005). Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov. 4, 307– 320. 10.1038/nrd1691 15789122 · DOI · Paper page
  117. Wang J. Xiang H. Lu Y. Wu T. Ji G. (2021). The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression. Am. J. Cancer Res. 11, 2477– 2494. 34249411 PMC8263643
  118. Wang L. Li C. Song Y. Yan Z. (2020). Inhibition of carnitine palmitoyl transferase 1A-induced fatty acid oxidation suppresses cell progression in gastric cancer. Arch. Biochem. Biophys. 696, 108664. 10.1016/j.abb.2020.108664 33157102 · DOI
  119. Wang Y. N. Zeng Z. L. Lu J. Wang Y. Liu Z. X. He M. M. (2018). CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 37, 6025– 6040. 10.1038/s41388-018-0384-z 29995871 · DOI
  120. Weber M. Mera P. Casas J. Salvador J. Rodriguez A. Alonso S. (2020). Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD. FASEB J. 34, 11816– 11837. 10.1096/fj.202000678R 32666604 · DOI
  121. Wen Y. A. Xing X. Harris J. W. Zaytseva Y. Y. Mitov M. I. Napier D. L. (2017). Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis. 8, e2593. 10.1038/cddis.2017.21 28151470 PMC5386470 · DOI
  122. Xie T. So W. Y. Li X. Y. Leung P. S. (2019). Fibroblast growth factor 21 protects against lipotoxicity-induced pancreatic beta-cell dysfunction via regulation of AMPK signaling and lipid metabolism. Clin. Sci. (Lond) 133, 2029– 2044. 10.1042/CS20190093 31654570 · DOI
  123. Xiong Y. Liu Z. Zhao X. Ruan S. Zhang X. Wang S. (2018). CPT1A regulates breast cancer-associated lymphangiogenesis via VEGF signaling. Biomed. Pharmacother. 106, 1– 7. 10.1016/j.biopha.2018.05.112 29940537 · DOI
  124. Yao C. H. Liu G. Y. Wang R. Moon S. H. Gross R. W. Patti G. J. (2018). Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of beta-oxidation. PLoS Biol. 16, e2003782. 10.1371/journal.pbio.2003782 29596410 PMC5892939 · DOI
  125. Yao Q. Li S. Cheng X. Zou Y. Shen Y. Zhang S. (2020). Yin Zhi Huang, a traditional Chinese herbal formula, ameliorates diet-induced obesity and hepatic steatosis by activating the AMPK/SREBP-1 and the AMPK/ACC/CPT1A pathways. Ann. Transl. Med. 8, 231. 10.21037/atm.2020.01.31 32309378 PMC7154390 · DOI
  126. Zeng F. Yao M. Wang Y. Zheng W. Liu S. Hou Z. (2022). Fatty acid beta-oxidation promotes breast cancer stemness and metastasis via the miRNA-328-3p-CPT1A pathway. Cancer Gene Ther. 29, 383– 395. 10.1038/s41417-021-00348-y 34045663 PMC8940624 · DOI
  127. Zhang Y. Ma K. Song S. Elam M. B. Cook G. A. Park E. A. (2004). Peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-I alpha). J. Biol. Chem. 279, 53963– 53971. 10.1074/jbc.M406028200 15469941 · DOI

Authors
Liang, K.
Affiliations
Peking University (CN)
Corresponding author
Liang, Kai
ORCID
Liang, Kai
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2023-03-23
Volume
14
Pages
1160440-1160440
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2023.1160440
PMC
PMC10076611
OpenAlex
W4360617433
Cited by
156
References
139
Citations by year
2026: 62 · 2025: 56 · 2024: 35 · 2023: 3
FWCI
4.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
CPT1A, fatty acid beta-oxidation, etomoxir, cancer metabolism, lipid metabolism, metabolic disorders, drug resistance, drug development

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review