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Journal of Molecular Medicine

, Volume 98, Issue 1, pp 71–95 | Cite as

The vital role of ATP citrate lyase in chronic diseases

  • Amrita Devi Khwairakpam
  • Kishore Banik
  • Sosmitha Girisa
  • Bano Shabnam
  • Mehdi Shakibaei
  • Lu Fan
  • Frank Arfuso
  • Javadi Monisha
  • Hong Wang
  • Xinliang Mao
  • Gautam SethiEmail author
  • Ajaikumar B. KunnumakkaraEmail author
Review
  • 197 Downloads

Abstract

Chronic or non-communicable diseases are the leading cause of death worldwide; they usually result in long-term illnesses and demand long-term care. Despite advances in molecular therapeutics, specific biomarkers and targets for the treatment of these diseases are required. The dysregulation of de novo lipogenesis has been found to play an essential role in cell metabolism and is associated with the development and progression of many chronic diseases; this confirms the link between obesity and various chronic diseases. The main enzyme in this pathway—ATP-citrate lyase (ACLY), a lipogenic enzyme—catalyzes the critical reaction linking cellular glucose catabolism and lipogenesis. Increasing lines of evidence suggest that the modulation of ACLY expression correlates with the development and progressions of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases, diabetes, obesity, inflammation, and cancer. Recent studies suggest that the inhibition of ACLY activity modulates the glycolysis and lipogenesis processes and stimulates normal physiological functions. This comprehensive review aimed to critically evaluate the role of ACLY in the development and progression of different diseases and the effects of its downregulation in the prevention and treatment of these diseases.

Keywords

Chronic diseases ATP citrate lyase Lipogenic enzyme Fatty acid biosynthesis 

Abbreviations

6PGD

6-phosphogluconate dehydrogenase

ACA

acetyl-CoA

ACACA

acetyl-CoA carboxylase

AACA

acetoacetyl-CoA

ACSS2

acyl-CoA synthetase short-chain family member 2

AFP

alpha-fetoprotein

AK

α-ketoglutarate

AMPK

5′ AMP-activated protein kinase

ATM

ataxia telangiectasia mutated

BDK

branched-chain alpha-keto acid dehydrogenase kinase

Bical

bicalutamide

CA

caffeic acid (trans-3,4-dihydroxycinnamic acid)

CES1

carboxylesterase

CHOP

CCAAT/enhancer-binding protein homologs protein

Cis

cisplatin

CPT1

carnitine palmitoyltransferase 1A

CS

citrate synthase

CuB

cucurbitacin B

CUL3

cullin3

ENO1

enolase 1

ENZ

enzalutamide

ELOVL6

fatty acyl-CoA elongase 6

ETV4

PEA3 transcription factor

FADS2

fatty acid desaturase

FAO

fatty acid β-oxidation

FAS

fatty acid synthase

FDPase

fructose-1, 6-diphosphatase

FBPase

fructose-1, 6-biophosphatase

GK

glucokinase

GPDH

glycerol 3-phosphate dehydrogenase

G6Pase

glucose-6-phosphatase

GS

glycogen synthase

GSIS

glucose-stimulated insulin secretion

HIF1α

hypoxia-inducible factor-1α

HCC

hepatocellular carcinoma

HCA

hydroxycitrate

HMG-CoA

−3-hydroxy-3-methylglutaryl-CoA

HK

hexokinase

HL

hyperlipidemia

IRK

insulin receptor kinase

LDH-A

lactate dehydrogenase A

LXR-s

liver X receptor-s

LA

lipoic acid

MAPK

mitogen-activated protein kinase

MCA

malonyl-CoA

ME

malic enzyme

MTX

methotrexate

NO

nitric oxide

OAA

oxaloacetate

OGDH

oxoglutarate dehydrogenase

ODK

oxidative decarboxylation of α-ketoglutarate

PC

pyruvate citrate

PD

pyruvate dehydrogenase

PDH

6-phosphogluconate dehydrogenase

PDHB

pyruvate dehydrogenase (lipoamide) beta

PEPCK

phosphoenolpyruvate carboxykinase

PFK-1

phosphofructokinase-1

PGE2

prostaglandin E2

PHP

protein histidine phosphatase

PI3K

phosphatidylinositol-3-kinase

PK

pyruvate kinase

PPAR-γ

peroxisome proliferator-activated receptor gamma

PUFA

polyunsaturated fatty acid

RAD

radicicol

RBP-1

retinol-binding protein 1

RIPK3

receptor-interacting protein kinase-3

ROS

reactive oxygen species

SCOT

succinyl-CoA:3-ketoacid-CoA transferase

SCD1

stearoyl-CoA desaturase-1

SOV

sodium-orthovanadate

SREBP-1

sterol regulatory element-binding protein-1

SREBF-2

sterol regulatory element-binding factor 2

T3

triiodothyronine

TF4

transcription factor 4

TG

triglyceride

TSP

Trigonella foenum graecum Linn

USP13

ubiquitin-specific peptidase 13

Notes

Acknowledgments

This work was supported by the project (No. BT/BI/14/042/2017) by the Department of Biotechnology (DBT), Government of India, awarded to Dr. Ajaikumar B. Kunnumakkara, DBT-AIST International Laboratory for Advanced Biomedicine, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam, India. Kishore Banik acknowledges the UGC, New Delhi, India, for the fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Bauer UE, Briss PA, Goodman RA, Bowman BA (2014) Prevention of chronic disease in the 21st century: elimination of the leading preventable causes of premature death and disability in the USA. Lancet (London, England) 384(9937):45–52Google Scholar
  2. 2.
    Meetoo D (2008) Chronic diseases: the silent global epidemic. British journal of nursing (Mark Allen Publishing, London) 17(21):1320–1325. Google Scholar
  3. 3.
    Kunnumakkara AB, Banik K, Bordoloi D, Harsha C, Sailo BL, Padmavathi G, Roy NK, Gupta SC, Aggarwal BB (2018) Googling the Guggul (Commiphora and Boswellia) for prevention of chronic diseases. Front Pharmacol 9:686PubMedPubMedCentralGoogle Scholar
  4. 4.
    Singh YP, Girisa S, Banik K, Ghosh S, Swathi P, Deka M, Padmavathi G, Kotoky J, Sethi G, Fan L et al (2019) Potential application of zerumbone in the prevention and therapy of chronic human diseases. J Funct Foods 53:248–258Google Scholar
  5. 5.
    Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY (2019) Signal transducer and activator of transcription (stats) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol 9:48PubMedPubMedCentralGoogle Scholar
  6. 6.
    Wee I, Syn N, Sethi G, Goh BC, Wang L (2019) Role of tumor-derived exosomes in cancer metastasis. Biochim Biophys Acta Rev Cancer. 1871(1):12–19PubMedGoogle Scholar
  7. 7.
    Wang C, Kar S, Lai X, Cai W, Arfuso F, Sethi G, Lobie PE, Goh BC, Lim LHK, Hartman M et al (2018) Triple negative breast cancer in Asia: an insider’s view. Cancer Treat Rev 62:29–38PubMedGoogle Scholar
  8. 8.
    Shanmugam MK, Kannaiyan R, Sethi G (2011) Targeting cell signaling and apoptotic pathways by dietary agents: role in the prevention and treatment of cancer. Nutr Cancer 63(2):161–173PubMedGoogle Scholar
  9. 9.
    Xue B, Sukumaran S, Nie J, Jusko WJ, Dubois DC, Almon RR (2011) Adipose tissue deficiency and chronic inflammation in diabetic Goto-Kakizaki rats. PLoS One 6(2):e17386PubMedPubMedCentralGoogle Scholar
  10. 10.
    Kunnumakkara AB, Sailo BL, Banik K, Harsha C, Prasad S, Gupta SC, Bharti AC, Aggarwal BB (2018) Chronic diseases, inflammation, and spices: how are they linked? J Transl Med 16(1):14PubMedPubMedCentralGoogle Scholar
  11. 11.
    Harsha C, Banik K, Bordoloi D, Kunnumakkara AB (2017) Antiulcer properties of fruits and vegetables: a mechanism based perspective. Food and chemical toxicology : an international journal published for the British. Industrial Biological Research Association 108(Pt A):104–119Google Scholar
  12. 12.
    Singh SS, Vats S, Chia AY, Tan TZ, Deng S, Ong MS, Arfuso F, Yap CT, Goh BC, Sethi G et al (2018) Dual role of autophagy in hallmarks of cancer. Oncogene 37(9):1142–1158PubMedGoogle Scholar
  13. 13.
    Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, Bishayee A, Ahn KS (2017) The role of resveratrol in cancer therapy. Int J Mol Sci 18(12).  https://doi.org/10.3390/ijms18122589 PubMedCentralGoogle Scholar
  14. 14.
    Shanmugam MK, Warrier S, Kumar AP, Sethi G, Arfuso F (2017) Potential role of natural compounds as anti-angiogenic agents in cancer. Curr Vasc Pharmacol 15(6):503–519PubMedGoogle Scholar
  15. 15.
    Cheong DHJ, Arfuso F, Sethi G, Wang L, Hui KM, Kumar AP, Tran T (2018) Molecular targets and anti-cancer potential of escin. Cancer Lett 422:1–8PubMedGoogle Scholar
  16. 16.
    Bishayee A, Sethi G (2016) Bioactive natural products in cancer prevention and therapy: progress and promise. Semin Cancer Biol 40–41:1–3PubMedGoogle Scholar
  17. 17.
    Shanmugam MK, Lee JH, Chai EZ, Kanchi MM, Kar S, Arfuso F, Dharmarajan A, Kumar AP, Ramar PS, Looi CY et al (2016) Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Semin Cancer Biol 40–41:35–47PubMedGoogle Scholar
  18. 18.
    Chua AW, Hay HS, Rajendran P, Shanmugam MK, Li F, Bist P, Koay ES, Lim LH, Kumar AP, Sethi G (2010) Butein downregulates chemokine receptor CXCR4 expression and function through suppression of NF-kappaB activation in breast and pancreatic tumor cells. Biochem Pharmacol 80(10):1553–1562PubMedGoogle Scholar
  19. 19.
    Sethi G, Chatterjee S, Rajendran P, Li F, Shanmugam MK, Wong KF, Kumar AP, Senapati P, Behera AK, Hui KM et al (2014) Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo. Mol Cancer 13:66PubMedPubMedCentralGoogle Scholar
  20. 20.
    Nair AS, Shishodia S, Ahn KS, Kunnumakkara AB, Sethi G, Aggarwal BB (2006) Deguelin, an Akt inhibitor, suppresses IkappaBalpha kinase activation leading to suppression of NF-kappaB-regulated gene expression, potentiation of apoptosis, and inhibition of cellular invasion. J Immun (Baltimore, Md : 1950) 177(8):5612–5622Google Scholar
  21. 21.
    Ahn KS, Sethi G, Chaturvedi MM, Aggarwal BB (2008) Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway. Int J Cancer 123(8):1733–1740PubMedGoogle Scholar
  22. 22.
    Ahn KS, Sethi G, Aggarwal BB (2008) Reversal of chemoresistance and enhancement of apoptosis by statins through down-regulation of the NF-kappaB pathway. Biochem Pharmacol 75(4):907–913PubMedGoogle Scholar
  23. 23.
    Woo CC, Hsu A, Kumar AP, Sethi G, Tan KH (2013) Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS. PLoS One 8(10):e75356PubMedPubMedCentralGoogle Scholar
  24. 24.
    Shanmugam MK, Manu KA, Ong TH, Ramachandran L, Surana R, Bist P, Lim LH, Kumar AP, Hui KM, Sethi G (2011) Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model. Int J Cancer 129(7):1552–1563PubMedGoogle Scholar
  25. 25.
    Manu KA, Shanmugam MK, Ramachandran L, Li F, Fong CW, Kumar AP, Tan P, Sethi G (2012) First evidence that gamma-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-kappaB pathway. Clin Cancer Res 18(8):2220–2229PubMedGoogle Scholar
  26. 26.
    Nugent R (2008) Chronic diseases in developing countries: health and economic burdens. Ann N Y Acad Sci 1136:70–79PubMedGoogle Scholar
  27. 27.
    Kunnumakkara AB, Bordoloi D, Harsha C, Banik K, Gupta SC, Aggarwal BB (2017) Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clin Sci (London, England : 1979) 131(15):1781–1799Google Scholar
  28. 28.
    Banik K, Ranaware AM, Deshpande V, Nalawade SP, Padmavathi G, Bordoloi D, Sailo BL, Shanmugam MK, Fan L, Arfuso F et al (2019) Honokiol for cancer therapeutics: a traditional medicine that can modulate multiple oncogenic targets. Pharmacol Res 144:192–209PubMedGoogle Scholar
  29. 29.
    Ong SKL, Shanmugam MK, Fan L, Fraser SE, Arfuso F, Ahn KS, Sethi G, Bishayee A (2019) Focus on formononetin: anticancer potential and molecular targets. Cancers 11(5).  https://doi.org/10.3390/cancers11050611 PubMedCentralGoogle Scholar
  30. 30.
    Mishra S, Verma SS, Rai V, Awasthee N, Chava S, Hui KM, Kumar AP, Challagundla KB, Sethi G, Gupta SC (2019) Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases. Cell Mol Life Sci 76(10):1947–1966PubMedGoogle Scholar
  31. 31.
    Deng S, Shanmugam MK, Kumar AP, Yap CT, Sethi G, Bishayee A (2019) Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer 125(8):1228–1246PubMedGoogle Scholar
  32. 32.
    Jung YY, Hwang ST, Sethi G, Fan L, Arfuso F, Ahn KS (2018) Potential anti-inflammatory and anti-cancer properties of farnesol. Molecules (Basel, Switzerland) 23(11).  https://doi.org/10.3390/molecules23112827 PubMedCentralGoogle Scholar
  33. 33.
    Merarchi M, Sethi G, Fan L, Mishra S, Arfuso F, Ahn KS (2018) Molecular targets modulated by fangchinoline in tumor cells and preclinical models. Molecules (Basel, Switzerland) 23(10).  https://doi.org/10.3390/molecules23102538 PubMedCentralGoogle Scholar
  34. 34.
    Sethi G, Shanmugam MK, Warrier S, Merarchi M, Arfuso F, Kumar AP, Bishayee A (2018) Pro-apoptotic and anti-cancer properties of diosgenin: a comprehensive and critical review. Nutrients 10(5).  https://doi.org/10.3390/nu10050645 PubMedCentralGoogle Scholar
  35. 35.
    Shanmugam MK, Shen H, Tang FR, Arfuso F, Rajesh M, Wang L, Kumar AP, Bian J, Goh BC, Bishayee A et al (2018) Potential role of genipin in cancer therapy. Pharmacol Res 133:195–200PubMedGoogle Scholar
  36. 36.
    Banik K, Harsha C, Bordoloi D, Lalduhsaki Sailo B, Sethi G, Leong HC, Arfuso F, Mishra S, Wang L, Kumar AP et al (2018) Therapeutic potential of gambogic acid, a caged xanthone, to target cancer. Cancer Lett 416:75–86PubMedGoogle Scholar
  37. 37.
    Dai X, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS, Sethi G (2015) Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exper bio and med (Maywood, NJ) 240(6):760–773Google Scholar
  38. 38.
    Rajendran P, Li F, Shanmugam MK, Vali S, Abbasi T, Kapoor S, Ahn KS, Kumar AP, Sethi G (2012) Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1. J Cell Physiol 227(5):2184–2195PubMedGoogle Scholar
  39. 39.
    Tan SM, Li F, Rajendran P, Kumar AP, Hui KM, Sethi G (2010) Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J Pharmacol Exp Ther 334(1):285–293PubMedGoogle Scholar
  40. 40.
    Siveen KS, Ahn KS, Ong TH, Shanmugam MK, Li F, Yap WN, Kumar AP, Fong CW, Tergaonkar V, Hui KM et al (2014) Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget 5(7):1897–1911PubMedPubMedCentralGoogle Scholar
  41. 41.
    Rajendran P, Li F, Manu KA, Shanmugam MK, Loo SY, Kumar AP, Sethi G (2011) gamma-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent. Br J Pharmacol 163(2):283–298PubMedPubMedCentralGoogle Scholar
  42. 42.
    Saito M, Ueno M, Ogino S, Kubo K, Nagata J, Takeuchi M (2005) High dose of Garcinia cambogia is effective in suppressing fat accumulation in developing male Zucker obese rats, but highly toxic to the testis. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 43(3):411–419. Google Scholar
  43. 43.
    Zagayko AL, Shkapo AI, Fylymonenko VP, Briukhanova TO (2016) The impact of hydroxycitric acid on the lipid metabolism profile under experimental insulin resistance syndrome of Syrian hamsters. Ukrainian Biochem J 88(3):78–82Google Scholar
  44. 44.
    Li JJ, Wang H, Tino JA, Robl JA, Herpin TF, Lawrence RM, Biller S, Jamil H, Ponticiello R, Chen L et al (2007) 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg Med Chem Lett 17(11):3208–3211PubMedGoogle Scholar
  45. 45.
    Khwairakpam AD, Shyamananda MS, Sailo BL, Rathnakaram SR, Padmavathi G, Kotoky J, Kunnumakkara AB (2015) ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. Curr Drug Targets 16(2):156–163PubMedGoogle Scholar
  46. 46.
    Ma Z, Chu CH, Cheng D (2009) A novel direct homogeneous assay for ATP citrate lyase. J Lipid Res 50(10):2131–2135PubMedPubMedCentralGoogle Scholar
  47. 47.
    He Q, Wang M, Petucci C, Gardell SJ, Han X (2013) Rotenone induces reductive stress and triacylglycerol deposition in C2C12 cells. Int J Biochem Cell Biol 45(12):2749–2755PubMedGoogle Scholar
  48. 48.
    Beigneux AP, Kosinski C, Gavino B, Horton JD, Skarnes WC, Young SG (2004) ATP-citrate lyase deficiency in the mouse. J Biol Chem 279(10):9557–9564PubMedGoogle Scholar
  49. 49.
    Koerner SK, Hanai JI, Bai S, Jernigan FE, Oki M, Komaba C, Shuto E, Sukhatme VP, Sun L (2017) Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase. Eur J Med Chem 126:920–928PubMedGoogle Scholar
  50. 50.
    Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, Carrer A, Sengupta A, Campbell SL, Kuo YM et al (2016) ATP-Citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep 17(4):1037–1052PubMedPubMedCentralGoogle Scholar
  51. 51.
    Carrer A, Parris JL, Trefely S, Henry RA, Montgomery DC, Torres A, Viola JM, Kuo YM, Blair IA, Meier JL et al (2017) Impact of a high-fat diet on tissue Acyl-CoA and histone acetylation levels. J Biol Chem 292(8):3312–3322PubMedPubMedCentralGoogle Scholar
  52. 52.
    Gopal U, Pizzo SV (2017) Cell surface GRP78 promotes tumor cell histone acetylation through metabolic reprogramming: a mechanism which modulates the Warburg effect. Oncotarget 8(64):107947–107963PubMedPubMedCentralGoogle Scholar
  53. 53.
    Zhang H, Zhang L, Chen H, Chen YQ, Chen W, Song Y, Ratledge C (2014) Enhanced lipid accumulation in the yeast Yarrowia lipolytica by over-expression of ATP:citrate lyase from Mus musculus. J Biotechnol 192:Pt A:78–Pt A:84PubMedGoogle Scholar
  54. 54.
    Ma TT, Huang C, Ni Y, Yang Y, Li J (2018) ATP citrate lyase and LncRNA NONMMUT010685 play crucial role in nonalcoholic fatty liver disease based on analysis of microarray data. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 51(2):871–885. Google Scholar
  55. 55.
    Zhang C, Liu J, Huang G, Zhao Y, Yue X, Wu H, Li J, Zhu J, Shen Z, Haffty BG et al (2016) Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev 30(17):1956–1970PubMedPubMedCentralGoogle Scholar
  56. 56.
    Xin M, Qiao Z, Li J, Liu J, Song S, Zhao X, Miao P, Tang T, Wang L, Liu W et al (2016) miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer. Oncotarget 7(28):44252–44265PubMedPubMedCentralGoogle Scholar
  57. 57.
    Singh M, Richards EG, Mukherjee A, Srere PA (1976) Structure of ATP citrate lyase from rat liver. Physicochemical studies and proteolytic modification. J Biol Chem 251(17):5242–5250PubMedGoogle Scholar
  58. 58.
    Elshourbagy NA, Near JC, Kmetz PJ, Sathe GM, Southan C, Strickler JE, Gross M, Young JF, Wells TN, Groot PH (1990) Rat ATP citrate-lyase. Molecular cloning and sequence analysis of a full-length cDNA and mRNA abundance as a function of diet, organ, and age. J Biol Chem 265(3):1430–1435PubMedGoogle Scholar
  59. 59.
    Sanchez LB, Galperin MY, Muller M (2000) Acetyl-CoA synthetase from the amitochondriate eukaryote Giardia lamblia belongs to the newly recognized superfamily of acyl-CoA synthetases (Nucleoside diphosphate-forming). J Biol Chem 275(8):5794–5803PubMedGoogle Scholar
  60. 60.
    Pinkosky SL, Groot PHE, Lalwani ND, Steinberg GR (2017) Targeting ATP-citrate lyase in hyperlipidemia and metabolic disorders. Trends Mol Med 23(11):1047–1063PubMedGoogle Scholar
  61. 61.
    Wei J, Leit S, Kuai J, Therrien E, Rafi S, Harwood HJ Jr, DeLaBarre B, Tong L (2019) An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature 568(7753):566–570PubMedGoogle Scholar
  62. 62.
    Verschueren KHG, Blanchet C, Felix J, Dansercoer A, De Vos D, Bloch Y, Van Beeumen J, Svergun D, Gutsche I, Savvides SN et al (2019) Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature 568(7753):571–575PubMedGoogle Scholar
  63. 63.
    Wojnarowicz PM, Breznan A, Arcand SL, Filali-Mouhim A, Provencher DM, Mes-Masson AM, Tonin PN (2008) Construction of a chromosome 17 transcriptome in serous ovarian cancer identifies differentially expressed genes. Int J Gynecol Cancer 18(5):963–975PubMedGoogle Scholar
  64. 64.
    Elshourbagy NA, Near JC, Kmetz PJ, Wells TN, Groot PH, Saxty BA, Hughes SA, Franklin M, Gloger IS (1992) Cloning and expression of a human ATP-citrate lyase cDNA. Eur J Biochem 204(2):491–499PubMedGoogle Scholar
  65. 65.
    Sun T, Hayakawa K, Bateman KS, Fraser ME (2010) Identification of the citrate-binding site of human ATP-citrate lyase using X-ray crystallography. J Biol Chem 285(35):27418–27428PubMedPubMedCentralGoogle Scholar
  66. 66.
    Bazilevsky GA, Affronti HC, Wei X, Campbell SL, Wellen KE, Marmorstein R (2019) ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis. J Biol Chem 294(18):7259–7268PubMedGoogle Scholar
  67. 67.
    Hu J, Komakula A, Fraser ME (2017) Binding of hydroxycitrate to human ATP-citrate lyase. Acta Crystallogr D Struct Biol 73(Pt 8):660–671Google Scholar
  68. 68.
    Fan F, Williams HJ, Boyer JG, Graham TL, Zhao H, Lehr R, Qi H, Schwartz B, Raushel FM, Meek TD (2012) On the catalytic mechanism of human ATP citrate lyase. Biochemistry 51(25):5198–5211PubMedGoogle Scholar
  69. 69.
    Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY (2013) Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell 51(4):506–518PubMedPubMedCentralGoogle Scholar
  70. 70.
    Dulermo T, Lazar Z, Dulermo R, Rakicka M, Haddouche R, Nicaud JM (2015) Analysis of ATP-citrate lyase and malic enzyme mutants of Yarrowia lipolytica points out the importance of mannitol metabolism in fatty acid synthesis. Biochim Biophys Acta 1851(9):1107–1117PubMedGoogle Scholar
  71. 71.
    Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science (New York, NY) 324(5930):1076–1080Google Scholar
  72. 72.
    Teng L, Chen Y, Cao Y, Wang W, Xu Y, Wang Y, Lv J, Li C, Su Y (2018) Overexpression of ATP citrate lyase in renal cell carcinoma tissues and its effect on the human renal carcinoma cells in vitro. Oncol Lett 15(5):6967–6974PubMedPubMedCentralGoogle Scholar
  73. 73.
    Chu KY, Lin Y, Hendel A, Kulpa JE, Brownsey RW, Johnson JD (2010) ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta cells. J Biol Chem 285(42):32606–32615PubMedPubMedCentralGoogle Scholar
  74. 74.
    Hildebrandt LA, Spennetta T, Elson C, Shrago E (1995) Utilization and preferred metabolic pathway of ketone bodies for lipid synthesis by isolated rat hepatoma cells. Am J Phys 269(1 Pt 1):C22–C27Google Scholar
  75. 75.
    Daikuhara Y, Tsunemi T, Takeda Y (1968) The role of ATP citrate lyase in the transfer of acetyl groups in rat liver. Biochim Biophys Acta 158(1):51–61PubMedGoogle Scholar
  76. 76.
    Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, Ushijima M, Mashima T, Seimiya H, Satoh Y et al (2008) ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 68(20):8547–8554PubMedGoogle Scholar
  77. 77.
    Zu XY, Zhang QH, Liu JH, Cao RX, Zhong J, Yi GH, Quan ZH, Pizzorno G (2012) ATP citrate lyase inhibitors as novel cancer therapeutic agents. Recent Pat Anticancer Drug Discov 7(2):154–167PubMedGoogle Scholar
  78. 78.
    Chypre M, Zaidi N, Smans K (2012) ATP-citrate lyase: a mini-review. Biochem Biophys Res Commun 422(1):1–4PubMedGoogle Scholar
  79. 79.
    Granchi C (2018) ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism. Eur J Med Chem 157:1276–1291PubMedGoogle Scholar
  80. 80.
    Zaidi N, Swinnen JV, Smans K (2012) ATP-citrate lyase: a key player in cancer metabolism. Cancer Res 72(15):3709–3714PubMedGoogle Scholar
  81. 81.
    Knowles LM, Yang C, Osterman A, Smith JW (2008) Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. J Biol Chem 283(46):31378–31384PubMedPubMedCentralGoogle Scholar
  82. 82.
    Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S et al (2014) Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 20(2):306–319PubMedPubMedCentralGoogle Scholar
  83. 83.
    El Azzouny M, Longacre MJ, Ansari IH, Kennedy RT, Burant CF, MacDonald MJ (2016) Knockdown of ATP citrate lyase in pancreatic beta cells does not inhibit insulin secretion or glucose flux and implicates the acetoacetate pathway in insulin secretion. Molecular metabolism 5(10):980–987PubMedPubMedCentralGoogle Scholar
  84. 84.
    Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR, Oliver-Williams C, Wood AM, Butterworth AS, Di Angelantonio E et al (2019) Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med 380(11):1033–1042PubMedGoogle Scholar
  85. 85.
    Rodriguez S, Denby CM, Van Vu T, Baidoo EE, Wang G, Keasling JD (2016) ATP citrate lyase mediated cytosolic acetyl-CoA biosynthesis increases mevalonate production in Saccharomyces cerevisiae. Microb Cell Factories 15:48Google Scholar
  86. 86.
    Rathmell JC, Newgard CB (2009) Biochemistry. A glucose-to-gene link. Science (New York, NY) 324(5930):1021–1022Google Scholar
  87. 87.
    Abramson HN (2011) The lipogenesis pathway as a cancer target. J Med Chem 54(16):5615–5638PubMedGoogle Scholar
  88. 88.
    Dolle RE, McNair D, Hughes MJ, Kruse LI, Eggelston D, Saxty BA, Wells TN, Groot PH (1992) ATP-citrate lyase as a target for hypolipidemic intervention. Sulfoximine and 3-hydroxy-beta-lactam containing analogues of citric acid as potential tight-binding inhibitors. J Med Chem 35(26):4875–4884PubMedGoogle Scholar
  89. 89.
    Namgaladze D, Zukunft S, Schnutgen F, Kurrle N, Fleming I, Fuhrmann D, Brune B (2018) Polarization of human macrophages by interleukin-4 does not require ATP-citrate lyase. Front Immunol 9:2858PubMedPubMedCentralGoogle Scholar
  90. 90.
    Lee JV, Berry CT, Kim K, Sen P, Kim T, Carrer A, Trefely S, Zhao S, Fernandez S, Barney LE et al (2018) Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca(2+)-NFAT signaling. Genes Dev 32(7–8):497–511PubMedPubMedCentralGoogle Scholar
  91. 91.
    Sivanand S, Rhoades S, Jiang Q, Lee JV, Benci J, Zhang J, Yuan S, Viney I, Zhao S, Carrer A et al (2017) Nuclear Acetyl-CoA production by ACLY promotes homologous recombination. Mol Cell 67(2):252–265.e256PubMedPubMedCentralGoogle Scholar
  92. 92.
    Migita T, Okabe S, Ikeda K, Igarashi S, Sugawara S, Tomida A, Soga T, Taguchi R, Seimiya H (2014) Inhibition of ATP citrate lyase induces triglyceride accumulation with altered fatty acid composition in cancer cells. Int J Cancer 135(1):37–47PubMedGoogle Scholar
  93. 93.
    Sato R, Okamoto A, Inoue J, Miyamoto W, Sakai Y, Emoto N, Shimano H, Maeda M (2000) Transcriptional regulation of the ATP citrate-lyase gene by sterol regulatory element-binding proteins. J Biol Chem 275(17):12497–12502PubMedGoogle Scholar
  94. 94.
    Shimano H (2002) Sterol regulatory element-binding protein family as global regulators of lipid synthetic genes in energy metabolism. Vitam Horm 65:167–194PubMedGoogle Scholar
  95. 95.
    Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK, Saxena NK, Biswal S, Girnun GD (2012) Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila) 5(4):544–552Google Scholar
  96. 96.
    Lee JH, Jang H, Lee SM, Lee JE, Choi J, Kim TW, Cho EJ, Youn HD (2015) ATP-citrate lyase regulates cellular senescence via an AMPK- and p53-dependent pathway. FEBS J 282(2):361–371PubMedGoogle Scholar
  97. 97.
    Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8(4):311–321PubMedGoogle Scholar
  98. 98.
    Sanchez-Solana B, Li DQ, Kumar R (2014) Cytosolic functions of MORC2 in lipogenesis and adipogenesis. Biochim Biophys Acta 1843(2):316–326PubMedGoogle Scholar
  99. 99.
    Ramakrishna S, Pucci DL, Benjamin WB (1981) ATP-citrate lyase kinase and cyclic AMP-dependent protein kinase phosphorylate different sites on ATP-citrate lyase. J Biol Chem 256(20):10213–10216PubMedGoogle Scholar
  100. 100.
    Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM (2002) The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem 277(37):33895–33900PubMedGoogle Scholar
  101. 101.
    Chen Y, Qian J, He Q, Zhao H, Toral-Barza L, Shi C, Zhang X, Wu J, Yu K (2016) mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget 7(18):25224–25240PubMedPubMedCentralGoogle Scholar
  102. 102.
    Das S, Morvan F, Jourde B, Meier V, Kahle P, Brebbia P, Toussaint G, Glass DJ, Fornaro M (2015) ATP citrate lyase improves mitochondrial function in skeletal muscle. Cell Metab 21(6):868–876PubMedGoogle Scholar
  103. 103.
    Li H, Sartorelli V (2018) ATP citrate lyase: a new player linking skeletal muscle metabolism and epigenetics. Trends Endocrinol Metab 29(4):202–204PubMedPubMedCentralGoogle Scholar
  104. 104.
    Potapova IA, El-Maghrabi MR, Doronin SV, Benjamin WB (2000) Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39(5):1169–1179PubMedGoogle Scholar
  105. 105.
    Hughes K, Ramakrishna S, Benjamin WB, Woodgett JR (1992) Identification of multifunctional ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3. The Biochem J 288(Pt 1):309–314PubMedGoogle Scholar
  106. 106.
    Lucenay KS, Doostan I, Karakas C, Bui T, Ding Z, Mills GB, Hunt KK, Keyomarsi K (2016) Cyclin E associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells. Cancer Res 76(8):2406–2418PubMedPubMedCentralGoogle Scholar
  107. 107.
    Tuhackova Z, Krivanek J (1996) GTP, a nonsubstrate of ATP citrate lyase, is a phosphodonor for the enzyme histidine autophosphorylation. Biochem Biophys Res Commun 218(1):61–66PubMedGoogle Scholar
  108. 108.
    White PJ, McGarrah RW, Grimsrud PA, Tso SC, Yang WH, Haldeman JM, Grenier-Larouche T, An J, Lapworth AL, Astapova I et al (2018) The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metab 27(6):1281–1293.e1287PubMedPubMedCentralGoogle Scholar
  109. 109.
    Keenan MM, Liu B, Tang X, Wu J, Cyr D, Stevens RD, Ilkayeva O, Huang Z, Tollini LA, Murphy SK et al (2015) ACLY and ACC1 regulate hypoxia-induced apoptosis by modulating ETV4 via alpha-ketoglutarate. PLoS Genet 11(10):e1005599PubMedPubMedCentralGoogle Scholar
  110. 110.
    Xu H, Luo J, Ma G, Zhang X, Yao D, Li M, Loor JJ (2018) Acyl-CoA synthetase short-chain family member 2 (ACSS2) is regulated by SREBP-1 and plays a role in fatty acid synthesis in caprine mammary epithelial cells. J Cell Physiol 233(2):1005–1016PubMedGoogle Scholar
  111. 111.
    Das S, Morvan F, Morozzi G, Jourde B, Minetti GC, Kahle P, Rivet H, Brebbia P, Toussaint G, Glass DJ et al (2017) ATP citrate lyase regulates myofiber differentiation and increases regeneration by altering histone acetylation. Cell Rep 21(11):3003–3011PubMedGoogle Scholar
  112. 112.
    Rhee J, Solomon LA, DeKoter RP (2019) A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation. Blood Cells Mol Dis 76:82–90PubMedGoogle Scholar
  113. 113.
    Steeg PS, Horak CE, Miller KD (2008) Clinical-translational approaches to the Nm23-H1 metastasis suppressor. Clin Cancer Res 14(16):5006–5012PubMedPubMedCentralGoogle Scholar
  114. 114.
    Wagner PD, Vu ND (2000) Histidine to aspartate phosphotransferase activity of nm23 proteins: phosphorylation of aldolase C on Asp-319. The Biochem J 346(Pt 3):623–630PubMedGoogle Scholar
  115. 115.
    Wagner PD, Steeg PS, Vu ND (1997) Two-component kinase-like activity of nm23 correlates with its motility-suppressing activity. Proceedings of the National Academy of Sciences of the United States of America 94(17):9000–9005Google Scholar
  116. 116.
    Tosukhowong P, Borvonpadungkitti S, Prasongwatana V, Tungsanga K, Jutuporn S, Dissayabutr T, Reungjui S, Sriboonlue P (2002) Urinary citrate excretion in patients with renal stone: roles of leucocyte ATP citrate lyase activity and potassium salts therapy. Clin Chim Acta 325(1–2):71–78PubMedGoogle Scholar
  117. 117.
    Hanai JI, Doro N, Seth P, Sukhatme VP (2013) ATP citrate lyase knockdown impacts cancer stem cells in vitro. Cell Death Dis 4:e696PubMedPubMedCentralGoogle Scholar
  118. 118.
    Carrer A, Trefely S, Zhao S, Campbell SL, Norgard RJ, Schultz KC, Sidoli S, Parris JLD, Affronti HC, Sivanand S et al (2019) Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Dis 9(3):416–435Google Scholar
  119. 119.
    Joseph JW, Odegaard ML, Ronnebaum SM, Burgess SC, Muehlbauer J, Sherry AD, Newgard CB (2007) Normal flux through ATP-citrate lyase or fatty acid synthase is not required for glucose-stimulated insulin secretion. J Biol Chem 282(43):31592–31600PubMedGoogle Scholar
  120. 120.
    Imamura M, Moon JS, Chung KP, Nakahira K, Muthukumar T, Shingarev R, Ryter SW, Choi AM, Choi ME (2018) RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase. JCI insight 3(3).  https://doi.org/10.1172/jci.insight.94979
  121. 121.
    Tyszka-Czochara M, Konieczny P, Majka M (2017) Caffeic acid expands anti-tumor effect of metformin in human metastatic cervical carcinoma HTB-34 cells: implications of AMPK activation and impairment of fatty acids de novo biosynthesis. Int J Mol Sci 18(2).  https://doi.org/10.3390/ijms18020462 PubMedCentralGoogle Scholar
  122. 122.
    Sailo BL, Banik K, Padmavathi G, Javadi M, Bordoloi D, Kunnumakkara AB (2018) Tocotrienols: the promising analogues of vitamin E for cancer therapeutics. Pharmacol Res 130:259–272Google Scholar
  123. 123.
    Shabnam B, Padmavathi G, Banik K, Girisa S, Monisha J, Sethi G, Fan L, Wang L, Mao X, Kunnumakkara AB (2018) Sorcin a potential molecular target for cancer therapy. Transl Oncol 11(6):1379–1389PubMedPubMedCentralGoogle Scholar
  124. 124.
    Kunnumakkara AB, Bordoloi D, Sailo BL, Roy NK, Thakur KK, Banik K, Shakibaei M, Gupta SC, Aggarwal BB (2019) Cancer drug development: the missing links. Exper bio and med (Maywood, NJ) 244(8):663–689Google Scholar
  125. 125.
    Tewari D, Nabavi SF, Nabavi SM, Sureda A, Farooqi AA, Atanasov AG, Vacca RA, Sethi G, Bishayee A (2018) Targeting activator protein 1 signaling pathway by bioactive natural agents: possible therapeutic strategy for cancer prevention and intervention. Pharmacol Res 128:366–375PubMedGoogle Scholar
  126. 126.
    Swamy SG, Kameshwar VH, Shubha PB, Looi CY, Shanmugam MK, Arfuso F, Dharmarajan A, Sethi G, Shivananju NS, Bishayee A (2017) Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target Oncol 12(1):1–10PubMedGoogle Scholar
  127. 127.
    Patel SM, Nagulapalli Venkata KC, Bhattacharyya P, Sethi G, Bishayee A (2016) Potential of neem (Azadirachta indica L.) for prevention and treatment of oncologic diseases. Semin Cancer Biol 40–41:100–115PubMedGoogle Scholar
  128. 128.
    Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, Dowluru KS, Chintala R, Duddukuri GR (2016) Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 40–41:48–81PubMedGoogle Scholar
  129. 129.
    Mastron JK, Siveen KS, Sethi G, Bishayee A (2015) Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review. Anti-Cancer Drugs 26(5):475–486PubMedGoogle Scholar
  130. 130.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108PubMedPubMedCentralGoogle Scholar
  131. 131.
    Ranaware AM, Banik K, Deshpande V, Padmavathi G, Roy NK, Sethi G, Fan L, Kumar AP, Kunnumakkara AB (2018) Magnolol: a neolignan from the magnolia family for the prevention and treatment of cancer. Int J Mol Sci 19(8).  https://doi.org/10.3390/ijms19082362 PubMedCentralGoogle Scholar
  132. 132.
    Sailo BL, Banik K, Girisa S, Bordoloi D, Fan L, Halim CE, Wang H, Kumar AP, Zheng D, Mao X et al (2019) FBXW7 in cancer: what has been unraveled thus far? Cancers 11(2).  https://doi.org/10.3390/cancers11020246 PubMedCentralGoogle Scholar
  133. 133.
    Khwairakpam AD, Bordoloi D, Thakur KK, Monisha J, Arfuso F, Sethi G, Mishra S, Kumar AP, Kunnumakkara AB (2018) Possible use of Punica granatum (Pomegranate) in cancer therapy. Pharmacol Res 133:53–64PubMedGoogle Scholar
  134. 134.
    Qi F, Zhao L, Zhou A, Zhang B, Li A, Wang Z, Han J (2015) The advantages of using traditional Chinese medicine as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer. Bioscience trends 9(1):16–34PubMedGoogle Scholar
  135. 135.
    Osugi J, Yamaura T, Muto S, Okabe N, Matsumura Y, Hoshino M, Higuchi M, Suzuki H, Gotoh M (2015) Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer. Lung cancer (Amsterdam, Netherlands) 88(3):310–318Google Scholar
  136. 136.
    Mashima T, Seimiya H, Tsuruo T (2009) De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 100(9):1369–1372PubMedPubMedCentralGoogle Scholar
  137. 137.
    Khiewkamrop P, Phunsomboon P, Richert L, Pekthong D, Srisawang P (2018) Epistructured catechins, EGCG and EC facilitate apoptosis induction through targeting de novo lipogenesis pathway in HepG2 cells. Cancer Cell Int 18:46PubMedPubMedCentralGoogle Scholar
  138. 138.
    Jin X, Zhang KJ, Guo X, Myers R, Ye Z, Zhang ZP, Li XF, Yang HS, Xing JL (2014) Fatty acid synthesis pathway genetic variants and clinical outcome of non-small cell lung cancer patients after surgery. Asian Pacific J cancer prevent : APJCP 15(17):7097–7103Google Scholar
  139. 139.
    Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24(41):6314–6322PubMedGoogle Scholar
  140. 140.
    Wang D, Yin L, Wei J, Yang Z, Jiang G (2017) ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis. Tumour Biol 39(4):1010428317698338PubMedGoogle Scholar
  141. 141.
    Qian X, Hu J, Zhao J, Chen H (2015) ATP citrate lyase expression is associated with advanced stage and prognosis in gastric adenocarcinoma. Int J Clin Exp Med 8(5):7855–7860PubMedPubMedCentralGoogle Scholar
  142. 142.
    Szutowicz A, Kwiatkowski J, Angielski S (1979) Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. Br J Cancer 39(6):681–687PubMedPubMedCentralGoogle Scholar
  143. 143.
    Volinsky N, McCarthy CJ, von Kriegsheim A, Saban N, Okada-Hatakeyama M, Kolch W, Kholodenko BN (2015) Signalling mechanisms regulating phenotypic changes in breast cancer cells. Biosci Rep 35(2).  https://doi.org/10.1042/bsr20140172
  144. 144.
    Ozkaya AB, Ak H, Atay S, Aydin HH (2015) Targeting mitochondrial citrate transport in breast cancer cell lines. Anti Cancer Agents Med Chem 15(3):374–381Google Scholar
  145. 145.
    Migita T, Okabe S, Ikeda K, Igarashi S, Sugawara S, Tomida A, Taguchi R, Soga T, Seimiya H (2013) Inhibition of ATP citrate lyase induces an anticancer effect via reactive oxygen species: AMPK as a predictive biomarker for therapeutic impact. Am J Pathol 182(5):1800–1810PubMedGoogle Scholar
  146. 146.
    Zhou Y, Bollu LR, Tozzi F, Ye X, Bhattacharya R, Gao G, Dupre E, Xia L, Lu J, Fan F et al (2013) ATP citrate lyase mediates resistance of colorectal cancer cells to SN38. Mol Cancer Ther 12(12):2782–2791PubMedPubMedCentralGoogle Scholar
  147. 147.
    Xie S, Zhou F, Wang J, Cao H, Chen Y, Liu X, Zhang Z, Dai J, He X (2015) Functional polymorphisms of ATP citrate lyase gene predicts clinical outcome of patients with advanced colorectal cancer. World J of surg oncol 13:42Google Scholar
  148. 148.
    Board M, Newsholme E (1996) Hydroxycitrate causes altered pyruvate metabolism by tumorigenic cells. Biochem Mol Biol Int 40(5):1047–1056PubMedGoogle Scholar
  149. 149.
    Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K, Morris AJ, Sunkara M, Weiss HL, Lee EY et al (2012) Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res 72(6):1504–1517PubMedPubMedCentralGoogle Scholar
  150. 150.
    Turyn J, Schlichtholz B, Dettlaff-Pokora A, Presler M, Goyke E, Matuszewski M, Kmiec Z, Krajka K, Swierczynski J (2003) Increased activity of glycerol 3-phosphate dehydrogenase and other lipogenic enzymes in human bladder cancer. Horm Metab Res 35(10):565–569PubMedGoogle Scholar
  151. 151.
    Schwartz L, Abolhassani M, Guais A, Sanders E, Steyaert JM, Campion F, Israel M (2010) A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results. Oncol Rep 23(5):1407–1416PubMedGoogle Scholar
  152. 152.
    Cheng Y, Jia B, Wang Y, Wan S (2017) miR-133b acts as a tumor suppressor and negatively regulates ATP citrate lyase via PPARgamma in gastric cancer. Oncol Rep 38(5):3220–3226PubMedGoogle Scholar
  153. 153.
    Beckner ME, Fellows-Mayle W, Zhang Z, Agostino NR, Kant JA, Day BW, Pollack IF (2010) Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer 126(10):2282–2295PubMedPubMedCentralGoogle Scholar
  154. 154.
    Icard P, Lincet H (2016) The reduced concentration of citrate in cancer cells: an indicator of cancer aggressiveness and a possible therapeutic target. Drug Resist Updat 29:47–53PubMedGoogle Scholar
  155. 155.
    Szutowicz A, Morrison MR, Srere PA (1983) The enzymes of acetyl-CoA metabolism in differentiating cholinergic (s-20) and noncholinergic (NIE-115) neuroblastoma cells. J Neurochem 40(6):1664–1670PubMedGoogle Scholar
  156. 156.
    Tajima A, Murai N, Murakami Y, Iwamoto T, Migita T, Matsufuji S (2016) Polyamine regulating protein antizyme binds to ATP citrate lyase to accelerate acetyl-CoA production in cancer cells. Biochem Biophys Res Commun 471(4):646–651PubMedGoogle Scholar
  157. 157.
    Yahagi N, Shimano H, Hasegawa K, Ohashi K, Matsuzaka T, Najima Y, Sekiya M, Tomita S, Okazaki H, Tamura Y et al (2005) Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. European J Can (Oxford, England : 1990) 41(9):1316–1322Google Scholar
  158. 158.
    Wu YS, Bao DK, Dai JY, Chen C, Zhang HX, Yang Y, Xing JL, Huang XJ, Wan SG (2015) Polymorphisms in genes of the de novo lipogenesis pathway and overall survival of hepatocellular carcinoma patients undergoing transarterial chemoembolization. Asian Pac J Cancer Prev 16(3):1051–1056PubMedGoogle Scholar
  159. 159.
    Li Z, Li D, Choi EY, Lapidus R, Zhang L, Huang SM, Shapiro P, Wang H (2017) Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells. J Biol Chem 292(33):13890–13901PubMedPubMedCentralGoogle Scholar
  160. 160.
    Lligona-Trulla L, Arduini A, Aldaghlas TA, Calvani M, Kelleher JK (1997) Acetyl-L-carnitine flux to lipids in cells estimated using isotopomer spectral analysis. J Lipid Res 38(7):1454–1462PubMedGoogle Scholar
  161. 161.
    Berkhout TA, Havekes LM, Pearce NJ, Groot PH (1990) The effect of (-)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2. The Biochem J 272(1):181–186PubMedGoogle Scholar
  162. 162.
    Yuan Y, Li W, Li L, Yang X, Gu R, Liu H, Huang K, Yu Y (2009) Effects of tetrazanbigen on the protein expression in human hepatocellular carcinoma cell line QGY-7701. J Huazhong Univ Sci Technolog Med Sci 29(3):304–308PubMedGoogle Scholar
  163. 163.
    Csanadi A, Kayser C, Donauer M, Gumpp V, Aumann K, Rawluk J, Prasse A, zur Hausen A, Wiesemann S, Werner M et al (2015) Prognostic value of malic enzyme and ATP-citrate lyase in non-small cell lung cancer of the young and the elderly. PLoS One 10(5):e0126357PubMedPubMedCentralGoogle Scholar
  164. 164.
    Hanai J, Doro N, Sasaki AT, Kobayashi S, Cantley LC, Seth P, Sukhatme VP (2012) Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol 227(4):1709–1720PubMedPubMedCentralGoogle Scholar
  165. 165.
    Sun H, Zhu A, Zhang L, Zhang J, Zhong Z, Wang F (2015) Knockdown of PKM2 suppresses tumor growth and invasion in lung adenocarcinoma. Int J Mol Sci 16(10):24574–24587PubMedPubMedCentralGoogle Scholar
  166. 166.
    Gao Y, Islam MS, Tian J, Lui VW, Xiao D (2014) Inactivation of ATP citrate lyase by Cucurbitacin B: a bioactive compound from cucumber, inhibits prostate cancer growth. Cancer Lett 349(1):15–25PubMedGoogle Scholar
  167. 167.
    Singh KB, Kim SH, Hahm ER, Pore SK, Jacobs BL, Singh SV (2018) Prostate cancer chemoprevention by sulforaphane in a preclinical mouse model is associated with inhibition of fatty acid metabolism. Carcinogenesis 39(6):826–837PubMedPubMedCentralGoogle Scholar
  168. 168.
    Halliday KR, Fenoglio-Preiser C, Sillerud LO (1988) Differentiation of human tumors from nonmalignant tissue by natural-abundance 13C NMR spectroscopy. Magn Reson Med 7(4):384–411PubMedGoogle Scholar
  169. 169.
    Bertilsson H, Tessem MB, Flatberg A, Viset T, Gribbestad I, Angelsen A, Halgunset J (2012) Changes in gene transcription underlying the aberrant citrate and choline metabolism in human prostate cancer samples. Clin Cancer Res 18(12):3261–3269PubMedGoogle Scholar
  170. 170.
    Ahmad I, Mui E, Galbraith L, Patel R, Tan EH, Salji M, Rust AG, Repiscak P, Hedley A, Markert E et al (2016) Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proc Natl Acad Sci U S A 113(29):8290–8295PubMedPubMedCentralGoogle Scholar
  171. 171.
    Shah S, Carriveau WJ, Li J, Campbell SL, Kopinski PK, Lim HW, Daurio N, Trefely S, Won KJ, Wallace DC et al (2016) Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget 7(28):43713–43730PubMedPubMedCentralGoogle Scholar
  172. 172.
    Misra UK, Pizzo SV (2015) Activated alpha2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses. J Biol Chem 290(15):9571–9587PubMedPubMedCentralGoogle Scholar
  173. 173.
    Al-Saffar NM, Jackson LE, Raynaud FI, Clarke PA, Ramirez de Molina A, Lacal JC, Workman P, Leach MO (2010) The phosphoinositide 3-kinase inhibitor PI-103 downregulates choline kinase alpha leading to phosphocholine and total choline decrease detected by magnetic resonance spectroscopy. Cancer Res 70(13):5507–5517PubMedPubMedCentralGoogle Scholar
  174. 174.
    Wang Y, Wang Y, Shen L, Pang Y, Qiao Z, Liu P (2012) Prognostic and therapeutic implications of increased ATP citrate lyase expression in human epithelial ovarian cancer. Oncol Rep 27(4):1156–1162PubMedPubMedCentralGoogle Scholar
  175. 175.
    Han C, Yang L, Choi HH, Baddour J, Achreja A, Liu Y, Li Y, Li J, Wan G, Huang C et al (2016) Amplification of USP13 drives ovarian cancer metabolism. Nat Commun 7:13525PubMedPubMedCentralGoogle Scholar
  176. 176.
    Singh MK, Das BK, Choudhary S, Gupta D, Patil UK (2018) Diabetes and hepatocellular carcinoma: a pathophysiological link and pharmacological management. Biomed Pharmacother 106:991–1002PubMedGoogle Scholar
  177. 177.
    Zhou T, Xu X, Du M, Zhao T, Wang J (2018) A preclinical overview of metformin for the treatment of type 2 diabetes. Biomed Pharmacother 106:1227–1235PubMedGoogle Scholar
  178. 178.
    Bordoloi D, Banik K, Shabnam B, Padmavathi G, Monisha J, Arfuso F, Dharmarajan A, Mao X, Lim LHK, Wang L et al (2018) TIPE family of proteins and its implications in different chronic diseases. Int J Mol Sci 19(10).  https://doi.org/10.3390/ijms19102974 PubMedCentralGoogle Scholar
  179. 179.
    MacDonald MJ, Longacre MJ, Langberg EC, Tibell A, Kendrick MA, Fukao T, Ostenson CG (2009) Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes. Diabetologia 52(6):1087–1091PubMedPubMedCentralGoogle Scholar
  180. 180.
    Taketomi S, Tsuda M, Matsuo T, Iwatsuka H, Suzuoki Z (1973) Alterations of hepatic enzyme activities in KK and yellow KK mice with various diabetic states. Horm Metab Res 5(5):333–339PubMedGoogle Scholar
  181. 181.
    Park SW, Kim KS, Whang SK, Kim JS, Kim YS (1994) Induction of hepatic ATP-citrate lyase by insulin in diabetic rat--effects of insulin on the contents of enzyme and its mRNA in cytosol, and the transcriptional activity in nuclei. Yonsei Med J 35(1):25–33PubMedGoogle Scholar
  182. 182.
    Obrosova IG, Efimov AS, Velikii NN, Zimatkina TI, Moiseenok AG (1988) Enzyme systems of the substrate and cofactor supply of hyperlipogenesis in non-insulin-dependent diabetes. Biull Eksp Biol Med 105(5):549–552PubMedGoogle Scholar
  183. 183.
    Wang Q, Jiang L, Wang J, Li S, Yu Y, You J, Zeng R, Gao X, Rui L, Li W et al (2009) Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepa (Baltimore, Md) 49(4):1166–1175Google Scholar
  184. 184.
    Xu J, Yin L, Xu Y, Li Y, Zalzala M, Cheng G, Zhang Y (2014) Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels. PLoS One 9(10):e109663PubMedPubMedCentralGoogle Scholar
  185. 185.
    Deb DK, Chen Y, Sun J, Wang Y, Li YC (2017) ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene upregulation in mesangial cells. Am J Physiol Ren Physiol 313(2):F423–F429Google Scholar
  186. 186.
    Kamath V, Kyathanahalli CN, Jayaram B, Syed I, Olson LK, Ludwig K, Klumpp S, Krieglstein J, Kowluru A (2010) Regulation of glucose- and mitochondrial fuel-induced insulin secretion by a cytosolic protein histidine phosphatase in pancreatic beta-cells. Am J Phys Endocrinol Metab 299(2):E276–E286Google Scholar
  187. 187.
    McAnuff-Harding MA, Omoruyi FO, Asemota HN (2006) Intestinal disaccharidases and some renal enzymes in streptozotocin-induced diabetic rats fed sapogenin extract from bitter yam (Dioscorea polygonoides). Life Sci 78(22):2595–2600PubMedGoogle Scholar
  188. 188.
    Joseph PK, Subrahmanyam K (1972) Evaluation of the rate-limiting steps in the pathway of glucose metabolism in kidney cortex of normal, diabetic, cortisone-treated and growth hormone-treated rats. The Biochem J 128(5):1293–1301PubMedGoogle Scholar
  189. 189.
    Yadav UC, Moorthy K, Baquer NZ (2004) Effects of sodium-orthovanadate and Trigonella foenum-graecum seeds on hepatic and renal lipogenic enzymes and lipid profile during alloxan diabetes. J Biosci 29(1):81–91PubMedGoogle Scholar
  190. 190.
    Hasan NM, Longacre MJ, Seed Ahmed M, Kendrick MA, Gu H, Ostenson CG, Fukao T, MacDonald MJ (2010) Lower succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and ATP citrate lyase in pancreatic islets of a rat model of type 2 diabetes: knockdown of SCOT inhibits insulin release in rat insulinoma cells. Arch Biochem Biophys 499(1–2):62–68PubMedPubMedCentralGoogle Scholar
  191. 191.
    Novak Mircetic R, Slijepcevic M, Cetkovic-Cvrlje M, Svetina A (1999) Neonatal pancreas transplantation and liver enzyme activities in diabetic mice. Acta Diabetol 36(4):185–190PubMedGoogle Scholar
  192. 192.
    Michno A, Skibowska A, Raszeja-Specht A, Cwikowska J, Szutowicz A (2004) The role of adenosine triphosphate citrate lyase in the metabolism of acetyl coenzyme a and function of blood platelets in diabetes mellitus. Metab Clin Exp 53(1):66–72PubMedGoogle Scholar
  193. 193.
    Skibowska A, Raszeja-Specht A, Szutowicz A (2003) Platelet function and acetyl-coenzyme A metabolism in type 1 diabetes mellitus. Clin Chem Lab Med 41(9):1136–1143PubMedGoogle Scholar
  194. 194.
    Flamez D, Berger V, Kruhoffer M, Orntoft T, Pipeleers D, Schuit FC (2002) Critical role for cataplerosis via citrate in glucose-regulated insulin release. Diabetes 51(7):2018–2024PubMedGoogle Scholar
  195. 195.
    Atkinson LL, Kelly SE, Russell JC, Bar-Tana J, Lopaschuk GD (2002) MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR: LA-cp rats. Diabetes 51(5):1548–1555PubMedGoogle Scholar
  196. 196.
    Tobe K, Suzuki R, Aoyama M, Yamauchi T, Kamon J, Kubota N, Terauchi Y, Matsui J, Akanuma Y, Kimura S et al (2001) Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver. J Biol Chem 276(42):38337–38340PubMedGoogle Scholar
  197. 197.
    Sochor M, Baquer NZ, Ball MR, McLean P (1987) Regulation of enzymes of glucose metabolism and lipogenesis in diabetic rat liver by thyroid hormones. Biochem Int 15(3):619–627PubMedGoogle Scholar
  198. 198.
    Leandro JG, Espindola-Netto JM, Vianna MC, Gomez LS, DeMaria TM, Marinho-Carvalho MM, Zancan P, Paula Neto HA, Sola-Penna M (2016) Exogenous citrate impairs glucose tolerance and promotes visceral adipose tissue inflammation in mice. Br J Nutr 115(6):967–973PubMedGoogle Scholar
  199. 199.
    Martin KA, Mani MV, Mani A (2015) New targets to treat obesity and the metabolic syndrome. Eur J Pharmacol 763(Pt A):64–74PubMedPubMedCentralGoogle Scholar
  200. 200.
    Hastings IM, Hill WG (1990) Analysis of lines of mice selected for fat content. 2. Correlated responses in the activities of enzymes involved in lipogenesis. Genet Res 55(1):55–61PubMedGoogle Scholar
  201. 201.
    Belfiore F, Borzi V, Napoli E, Rabuazzo AM (1976) Enzymes related to lipogenesis in the adipose tissue of obese subjects. Metab Clin Exp 25(5):483–493PubMedGoogle Scholar
  202. 202.
    Pugazhenthi S, Angel JF, Khandelwal RL (1993) Effects of vanadate administration on the high sucrose diet-induced aberrations in normal rats. Mol Cell Biochem 122(1):69–75PubMedGoogle Scholar
  203. 203.
    Pomplun D, Voigt A, Schulz TJ, Thierbach R, Pfeiffer AF, Ristow M (2007) Reduced expression of mitochondrial frataxin in mice exacerbates diet-induced obesity. Proc Natl Acad Sci U S A 104(15):6377–6381PubMedPubMedCentralGoogle Scholar
  204. 204.
    Belfiore F, Iannello S (1995) Fatty acid synthesis from glutamate in the adipose tissue of normal subjects and obese patients: an enzyme study. Biochem Mol Med 54(1):19–25PubMedGoogle Scholar
  205. 205.
    MacDonald MJ, Longacre MJ, Warner TF, Thonpho A (2013) High level of ATP citrate lyase expression in human and rat pancreatic islets. Horm Metab Res 45(5):391–393PubMedGoogle Scholar
  206. 206.
    Swierczynski J, Zabrocka L, Goyke E, Raczynska S, Adamonis W, Sledzinski Z (2003) Enhanced glycerol 3-phosphate dehydrogenase activity in adipose tissue of obese humans. Mol Cell Biochem 254(1–2):55–59PubMedGoogle Scholar
  207. 207.
    Gutierrez-Repiso C, Rodriguez-Pacheco F, Garcia-Arnes J, Valdes S, Gonzalo M, Soriguer F, Moreno-Ruiz FJ, Rodriguez-Canete A, Gallego-Perales JL, Alcain-Martinez G et al (2015) The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance. Lab Invest 95(12):1409–1417PubMedGoogle Scholar
  208. 208.
    Pan QR, Ren YL, Liu WX, Hu YJ, Zheng JS, Xu Y, Wang G (2015) Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. Nutr Res (New York, NY) 35(7):576–584Google Scholar
  209. 209.
    Yan C, Yang H, Wang Y, Dong Y, Yu F, Wu Y, Wang W, Adaku U, Lutfy K, Friedman TC et al (2016) Increased glycogen synthase kinase-3beta and hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to glucocorticoid-induced mouse visceral adiposity. Int J Obes (Lond) (2005) 40(8):1233–1241PubMedGoogle Scholar
  210. 210.
    Fukuda H, Iritani N (1999) Regulation of ATP citrate-lyase gene expression in hepatocytes and adipocytes in normal and genetically obese rats. J Biochem 126(2):437–444PubMedGoogle Scholar
  211. 211.
    Pugazhenthi S, Hussain A, Yu B, Brownsey RW, Angel JF, Khandelwal RL (1995) Vanadate induces normolipidemia and a reduction in the levels of hepatic lipogenic enzymes in obese Zucker rat. Mol Cell Biochem 153(1–2):211–215PubMedGoogle Scholar
  212. 212.
    Pugazhenthi S, Angel JF, Khandelwal RL (1993) Effects of high sucrose diet on insulin-like effects of vanadate in diabetic rats. Mol Cell Biochem 122(1):77–84PubMedGoogle Scholar
  213. 213.
    Arai T, Hasegawa Y, Oki Y (1992) Changes in hepatic lipogenic enzyme activities in voles and mice treated with monosodium aspartate. Res Vet Sci 53(2):247–249PubMedGoogle Scholar
  214. 214.
    Jiang L, Wang Q, Yu Y, Zhao F, Huang P, Zeng R, Qi RZ, Li W, Liu Y (2009) Leptin contributes to the adaptive responses of mice to high-fat diet intake through suppressing the lipogenic pathway. PLoS One 4(9):e6884PubMedPubMedCentralGoogle Scholar
  215. 215.
    Lee P, Mori A, Coradini M, Mori N, Sagara F, Yamamoto I, Rand JS, Arai T (2013) Potential predictive biomarkers of obesity in Burmese cats. Vet J (London, England : 1997) 195(2):221–227Google Scholar
  216. 216.
    Ryaboshapkina M, Hammar M (2017) Human hepatic gene expression signature of non-alcoholic fatty liver disease progression, a meta-analysis. Sci Rep 7(1):12361PubMedPubMedCentralGoogle Scholar
  217. 217.
    Tallino S, Duffy M, Ralle M, Cortes MP, Latorre M, Burkhead JL (2015) Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem 26(10):996–1006PubMedPubMedCentralGoogle Scholar
  218. 218.
    Chung MY, Song JH, Lee J, Shin EJ, Park JH, Lee SH, Hwang JT, Choi HK (2019) Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. Molecular metabolism 19:34–48PubMedGoogle Scholar
  219. 219.
    Molusky MM, Hsieh J, Lee SX, Ramakrishnan R, Tascau L, Haeusler RA, Accili D, Tall AR (2018) Metformin and AMP kinase activation increase expression of the sterol transporters ABCG5/8 (ATP-Binding Cassette Transporter G5/G8) with potential antiatherogenic consequences. Arterioscler Thromb Vasc Biol 38(7):1493–1503PubMedPubMedCentralGoogle Scholar
  220. 220.
    Pinkosky SL, Filippov S, Srivastava RA, Hanselman JC, Bradshaw CD, Hurley TR, Cramer CT, Spahr MA, Brant AF, Houghton JL et al (2013) AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res 54(1):134–151PubMedPubMedCentralGoogle Scholar
  221. 221.
    Marino G, Pietrocola F, Kong Y, Eisenberg T, Hill JA, Madeo F, Kroemer G (2014) Dimethyl alpha-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy. Autophagy 10(5):930–932PubMedPubMedCentralGoogle Scholar
  222. 222.
    Karlstaedt A, Zhang X, Vitrac H, Harmancey R, Vasquez H, Wang JH, Goodell MA, Taegtmeyer H (2016) Oncometabolite d-2-hydroxyglutarate impairs alpha-ketoglutarate dehydrogenase and contractile function in rodent heart. Proceedings of the National Academy of Sciences of the United States of America 113(37):10436–10441. Google Scholar
  223. 223.
    Shara M, Ohia SE, Schmidt RE, Yasmin T, Zardetto-Smith A, Kincaid A, Bagchi M, Chatterjee A, Bagchi D, Stohs SJ (2004) Physico-chemical properties of a novel (-)-hydroxycitric acid extract and its effect on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological changes over a period of 90 days. Mol Cell Biochem 260(1–2):171–186PubMedGoogle Scholar
  224. 224.
    Samsoondar JP, Burke AC, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, Pinkosky SL, Newton RS, Huff MW (2017) Prevention of diet-induced metabolic dysregulation, inflammation, and atherosclerosis in Ldlr(-/-) mice by treatment with the ATP-citrate lyase inhibitor bempedoic acid. Arterioscler Thromb Vasc Biol 37(4):647–656PubMedGoogle Scholar
  225. 225.
    Teng CF, Wu HC, Hsieh WC, Tsai HW, Su IJ (2015) Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis. J Virol 89(1):605–614PubMedGoogle Scholar
  226. 226.
    Hajjou M, Norel R, Carver R, Marion P, Cullen J, Rogler LE, Rogler CE (2005) cDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV. J Med Virol 77(1):57–65PubMedGoogle Scholar
  227. 227.
    Infantino V, Iacobazzi V, Palmieri F, Menga A (2013) ATP-citrate lyase is essential for macrophage inflammatory response. Biochem Biophys Res Commun 440(1):105–111PubMedGoogle Scholar
  228. 228.
    Infantino V, Pierri CL, Iacobazzi V (2018) Metabolic routes in inflammation: the citrate pathway and its potential as therapeutic target. Curr Med Chem.  https://doi.org/10.2174/0929867325666180510124558 Google Scholar
  229. 229.
    Lee YJ, Jang YN, Han YM, Kim HM, Jeong JM, Son MJ, Jin CB, Kim HJ, Seo HS (2017) Caffeoylquinic acid-rich extract of Aster glehni F. Schmidt ameliorates nonalcoholic fatty liver through the regulation of PPARdelta and adiponectin in ApoE KO mice. PPAR Res 2017:3912567PubMedPubMedCentralGoogle Scholar
  230. 230.
    Ashbrook MJ, McDonough KL, Pituch JJ, Christopherson PL, Cornell TT, Selewski DT, Shanley TP, Blatt NB (2015) Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. Clin Exp Immunol 180(3):520–530PubMedPubMedCentralGoogle Scholar
  231. 231.
    Sahin K, Orhan C, Tuzcu M, Sahin N, Erten F, Juturu V (2018) Capsaicinoids improve consequences of physical activity. Toxicol Rep 5:598–607PubMedPubMedCentralGoogle Scholar
  232. 232.
    Maccioni RB, Gonzalez A, Andrade V, Cortes N, Tapia JP, Guzman-Martinez L (2018) Alzheimer s disease in the perspective of neuroimmunology. The open neurol jour 12:50–56Google Scholar
  233. 233.
    Tomaszewicz M, Rossner S, Schliebs R, Cwikowska J, Szutowicz A (2003) Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin. J Neurochem 87(2):318–324PubMedGoogle Scholar
  234. 234.
    Perry EK, Perry RH, Tomlinson BE, Blessed G, Gibson PH (1980) Coenzyme A-acetylating enzymes in Alzheimer’s disease: possible cholinergic ‘compartment’ of pyruvate dehydrogenase. Neurosci Lett 18(1):105–110PubMedGoogle Scholar
  235. 235.
    Mukhopadhyay D, Mukherjea M (1998) Role of fatty acid binding protein in the modulation of inhibitory effect of fatty acids on fatty acid synthase and ATP-citrate lyase in developing human brain. Indian J Biochem Biophys 35(5):296–302PubMedGoogle Scholar
  236. 236.
    Eissing A, Fischer D, Rauch I, Baumann A, Schebb NH, Karst U, Rose K, Klumpp S, Krieglstein J (2012) Acetylcholine content and viability of cholinergic neurons are influenced by the activity of protein histidine phosphatase. BMC Neurosci 13:31PubMedPubMedCentralGoogle Scholar
  237. 237.
    Kang S, Seo JH, Heo TH, Kim SJ (2013) Batten disease is linked to altered expression of mitochondria-related metabolic molecules. Neurochem Int 62(7):931–935PubMedGoogle Scholar
  238. 238.
    Wang Q, Li S, Jiang L, Zhou Y, Li Z, Shao M, Li W, Liu Y (2010) Deficiency in hepatic ATP-citrate lyase affects VLDL-triglyceride mobilization and liver fatty acid composition in mice. J Lipid Res 51(9):2516–2526PubMedPubMedCentralGoogle Scholar
  239. 239.
    Morciano P, Di Giorgio ML, Porrazzo A, Licursi V, Negri R, Rong Y, Cenci G (2019) Depletion of ATP-citrate lyase (ATPCL) affects chromosome integrity without altering histone acetylation in drosophila mitotic cells. Front Physiol 10:383PubMedPubMedCentralGoogle Scholar
  240. 240.
    Deng Z, Wong NK, Guo Z, Zou K, Xiao Y, Zhou Y (2019) Dehydrocurvularin is a potent antineoplastic agent irreversibly blocking ATP-citrate lyase: evidence from chemoproteomics. Chem Commun (Camb) 55(29):4194–4197Google Scholar
  241. 241.
    Zagelbaum NK, Yandrapalli S, Nabors C, Frishman WH (2019) Bempedoic acid (ETC-1002): ATP citrate lyase inhibitor: review of a first-in-class medication with potential benefit in statin-refractory cases. Cardiol Rev 27(1):49–56PubMedGoogle Scholar
  242. 242.
    Ki SW, Ishigami K, Kitahara T, Kasahara K, Yoshida M, Horinouchi S (2000) Radicicol binds and inhibits mammalian ATP citrate lyase. J Biol Chem 275(50):39231–39236PubMedGoogle Scholar
  243. 243.
    Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T et al (2016) Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30(1):147–160PubMedPubMedCentralGoogle Scholar
  244. 244.
    Pearce NJ, Yates JW, Berkhout TA, Jackson B, Tew D, Boyd H, Camilleri P, Sweeney P, Gribble AD, Shaw A et al (1998) The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. The Biochem J 334(Pt 1):113–119PubMedGoogle Scholar
  245. 245.
    Gribble AD, Ife RJ, Shaw A, McNair D, Novelli CE, Bakewell S, Shah VP, Dolle RE, Groot PH, Pearce N et al (1998) ATP-citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo. J Med Chem 41(19):3582–3595PubMedGoogle Scholar
  246. 246.
    Burke AC, Huff MW (2017) ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia. Curr Opin Lipidol 28(2):193–200Google Scholar
  247. 247.
    Bilen O, Ballantyne CM (2016) Bempedoic acid (ETC-1002): an investigational inhibitor of ATP citrate lyase. Curr Atheroscler Rep 18(10):61PubMedPubMedCentralGoogle Scholar
  248. 248.
    Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, Birch CM, Smith BK, Filippov S, Groot PHE et al (2016) Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun 7:13457PubMedPubMedCentralGoogle Scholar
  249. 249.
    Lemus HN, Mendivil CO (2015) Adenosine triphosphate citrate lyase: emerging target in the treatment of dyslipidemia. J Clin Lipid 9(3):384–389Google Scholar
  250. 250.
    Fu Y, Lu R, Cui J, Sun H, Yang H, Meng Q, Wu S, Aschner M, Li X, Chen R (2019) Inhibition of ATP citrate lyase (ACLY) protects airway epithelia from PM2.5-induced epithelial-mesenchymal transition. Ecotoxicol Environ Saf 167:309–316PubMedGoogle Scholar
  251. 251.
    Guais A, Baronzio G, Sanders E, Campion F, Mainini C, Fiorentini G, Montagnani F, Behzadi M, Schwartz L, Abolhassani M (2012) Adding a combination of hydroxycitrate and lipoic acid (METABLOC) to chemotherapy improves effectiveness against tumor development: experimental results and case report. Investig New Drugs 30(1):200–211Google Scholar
  252. 252.
    Zaidi N, Royaux I, Swinnen JV, Smans K (2012) ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms. Mol Cancer Ther 11(9):1925–1935PubMedGoogle Scholar
  253. 253.
    Cascales C, Martin-Sanz P, Pittner RA, Hopewell R, Brindley DN, Cascales M (1986) Effects of an antitumoural rhodium complex on thioacetamide-induced liver tumor in rats. Changes in the activities of ornithine decarboxylase, tyrosine aminotransferase and of enzymes involved in fatty acid and glycerolipid synthesis. Biochem Pharmacol 35(16):2655–2661PubMedGoogle Scholar
  254. 254.
    Duan FT, Qian F, Fang K, Lin KY, Wang WT, Chen YQ (2013) miR-133b, a muscle-specific microRNA, is a novel prognostic marker that participates in the progression of human colorectal cancer via regulation of CXCR4 expression. Mol Cancer 12:164PubMedPubMedCentralGoogle Scholar
  255. 255.
    Pinweha P, Rattanapornsompong K, Charoensawan V, Jitrapakdee S (2016) MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers. Comput Struct Biotechnol J 14:223–233PubMedPubMedCentralGoogle Scholar
  256. 256.
    Londono Gentile T, Lu C, Lodato PM, Tse S, Olejniczak SH, Witze ES, Thompson CB, Wellen KE (2013) DNMT1 is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation. Mol Cell Biol 33(19):3864–3878PubMedPubMedCentralGoogle Scholar
  257. 257.
    Tomasetti M, Nocchi L, Staffolani S, Manzella N, Amati M, Goodwin J, Kluckova K, Nguyen M, Strafella E, Bajzikova M et al (2014) MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function. Antioxid Redox Signal 21(15):2109–2125PubMedPubMedCentralGoogle Scholar
  258. 258.
    Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (2008) The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 15(2):261–271PubMedPubMedCentralGoogle Scholar
  259. 259.
    Koufaris C, Valbuena GN, Pomyen Y, Tredwell GD, Nevedomskaya E, Lau CH, Yang T, Benito A, Ellis JK, Keun HC (2016) Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells. Oncogene 35(21):2766–2776PubMedGoogle Scholar
  260. 260.
    Liu H, Huang X, Ye T (2018) MiR-22 down-regulates the proto-oncogene ATP citrate lyase to inhibit the growth and metastasis of breast cancer. Am J Transl Res 10(3):659–669PubMedPubMedCentralGoogle Scholar
  261. 261.
    Li G, Li M, Hu J, Lei R, Xiong H, Ji H, Yin H, Wei Q, Hu G (2017) The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis. Oncogene 36(7):989–998Google Scholar
  262. 262.
    Wilkins HM, Koppel S, Carl SM, Ramanujan S, Weidling I, Michaelis ML, Michaelis EK, Swerdlow RH (2016) Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J Neurochem 137(1):76–87PubMedPubMedCentralGoogle Scholar
  263. 263.
    Macdonald MJ, Hasan NM, Longacre MJ (2008) Studies with leucine, beta-hydroxybutyrate and ATP citrate lyase-deficient beta cells support the acetoacetate pathway of insulin secretion. Biochim Biophys Acta 1780(7–8):966–972PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & BioengineeringIndian Institute of Technology GuwahatiGuwahatiIndia
  2. 2.Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of MedicineLudwig-Maximilian-University, MunichMunichGermany
  3. 3.Department of Pharmacology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  4. 4.Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research InstituteCurtin UniversityPerthAustralia
  5. 5.Institute of Clinical PharmacologyGuangzhou University of Chinese MedicineGuangzhouChina
  6. 6.Department of Pharmacology, College of Pharmaceutical SciencesSoochow UniversitySuzhouChina

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