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The vital role of ATP citrate lyase in chronic diseases

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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.

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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

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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.

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  1. Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India

    Amrita Devi Khwairakpam, Kishore Banik, Sosmitha Girisa, Bano Shabnam, Javadi Monisha & Ajaikumar B. Kunnumakkara

  2. Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University, Munich, Pettenkoferstrasse 11, 80336, Munich, Germany

    Mehdi Shakibaei

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117 600, Singapore

    Lu Fan, Hong Wang & Gautam Sethi

  4. Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6009, Australia

    Frank Arfuso

  5. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou, 510405, China

    Xinliang Mao

  6. Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, 215123, Jiangsu, China

    Xinliang Mao

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  1. Amrita Devi Khwairakpam
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Khwairakpam, A.D., Banik, K., Girisa, S. et al. The vital role of ATP citrate lyase in chronic diseases. J Mol Med 98, 71–95 (2020). https://doi.org/10.1007/s00109-019-01863-0

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