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The role of dihydrosphingolipids in disease

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Abstract

Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3-ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1-phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10–15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest.

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Abbreviations

3-KR:

3-Ketosphinganine Reductase

4-HPR:

N-(4-Hydroxyphenyl) retinamideFenretinide

γ-TE:

γ-Tocotrienol

ACER3:

Alkaline ceramidase 3

ACSL5:

Acyl-coenzyme A synthase

ACSL5:

Δ20 acyl-coenzyme A synthase lacking exon 20

ADH:

Adiponectin hormone

AHA:

American Heart Association

Akt:

Protein kinase B

AMPK:

AMP activated protein kinase

BMI:

Body mass index

CAD:

Coronary artery disease

cAMP:

Cyclic adenosine 3ʹ,5ʹ-monophosphate

cDase:

Ceramidase

cdk2:

Cyclin dependent kinase 2

Cer:

Ceramide

CERKL:

Ceramide like kinase

CERK:

Ceramide kinase

CerS:

Ceramide synthase

CFTR:

Cystic fibrosis transmembrane conductance regulator

COX-2:

Cyclooxygenase 2

CRF:

Cardiorespiratory fitness

CTGF:

Connective tissue growth factor

CVD:

Cardiovascular disease

Des1:

Dihydroceramide desaturase 1

Des2:

Dihydroceramide desaturase 2

DhCer:

Dihydroceramide

DhSph:

Dihydrosphingosine/Dihydrosphinganine

DhS1P:

Dihydrosphingosine 1 phosphate/dihydrosphinganine 1 phosphate

EAP:

Ethanolamine phosphate

ER:

Endoplasmic reticulum

ERK:

Extracellular signal regulated kinases

FAK:

Focal adhesion kinase

FB1:

Fumonisin B 1

FFA:

Free fatty acid

HDAC2:

Histone deacetylase 2

HDL:

High density lipid

HepG2:

Human hepato-carcinoma cell

HIF1-α:

Hypoxia inducible factor 1-α

HOMA-IR:

Homestasis model of insulin resistance

HSP27:

Heat shock protein 27

HUVEC:

Human umblical endothelial cell

FTY720:

Fingolimod

IL-1:

Interleukin 1

IL-6:

Interleukin 6

JNK:

c-Jun N terminal kinase

LDL:

Low density lipid

LPS:

Lipopolysaccharide

LRS:

Lipidomic risk score

MAPK:

Mitogen activated protein kinases

MI:

Myocardial infarct

MnTBAP:

Manganese(III) tetrakis (4-benzoic acid) porphyrin

MTORC1:

Mammalian target of rapamycin complex 1

NADH:

Nicotinamide adenine nucleotide

NADPH:

Nicotinamide adenine nucleotide phosphate

NAFLD:

Non-alcoholic fatty liver disease

NFATC:

Nuclear factor of activated T cells

NK-kβ:

Nuclear factor kappa light chain enhancer of B cell

Nrf2:

Nuclear factor erythroid related factor 2

PDGF:

Platelet derived growth factor

PDT:

Photodynamic therapy

PeIF2α:

Phosphorylated eukaryotic translation initiation factors 2α

PERK:

PKR like endoplasmic reticulum kinase

PKCα:

Protein kinase Cα

PLD:

Phospholipase D

PPARγ:

Peroxisome proliferator-activated receptor γ

RAR:

Retinoic acid receptor

RMC:

Renal mesengial cell

ROS:

Reactive oxygen species

S6K:

Ribosomal protein S6 kinase

SAFHS:

San Antonio Family Heart Study

SEK-1:

Dual specificity mitogen activated protein kinase kinase 1

SD:

Sprague Dawley

SK 1 and 2:

Sphingosine kinase 1 and 2

S1P:

Sphingosine 1 phosphate

S1PP:

Sphingosine 1 phosphate phophatase

S1PR1–5:

Sphingosine 1 phosphate receptor 1–5

SPL:

Sphingosine 1 phosphate lyase

SPT:

Serine palmitoyltransferase

SPLTC1:

Serine palmitoyltransferase long chain base 1

SPTLC3:

Serine palmitoyltransferase long chain base 3

STEMI:

ST-segment elevation myocardial: infarct

SCC19:

Squamous cell carcinoma cell

T2DM:

Type 2 diabetes mellitus

TNF-α:

Tumour necrosis factor α

VEGF:

Vascular endothelial growth factor

WC:

Waist circumference

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Funding

This research was supported by National Health and Medical Research Council of Australia Program Grants (1092642) (BHW, DL, CR and DJK) and Project Grant (1087355) (BHW). RM and FS are sponsored by a Monash Graduate Scholarship and Monash International Postgraduate Research Scholarship for their doctoral studies.

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Authors and Affiliations

  1. Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

    Ruth. R. Magaye, Feby Savira, Yue Hua, Christopher Reid, Danny Liew & Bing H. Wang

  2. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia

    Darren J. Kelly

  3. Australian Translational Medicinal Chemistry Facility, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

    Bernard Flynn

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  1. Ruth. R. Magaye
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  2. Feby Savira
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  8. Bing H. Wang
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Contributions

RM and BW conceived and designed review question, conducted preliminary data search, and sorting the papers. FS and YH conducted literature search and screening. DK, CR, BF and DL assisted drafting and edited of the paper and had responsibility for its final content. All authors read and approved the final manuscript.

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Correspondence to Bing H. Wang.

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Magaye, R.R., Savira, F., Hua, Y. et al. The role of dihydrosphingolipids in disease. Cell. Mol. Life Sci. 76, 1107–1134 (2019). https://doi.org/10.1007/s00018-018-2984-8

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