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The role of dihydrosphingolipids in disease

  • Ruth. R. Magaye
  • Feby Savira
  • Yue Hua
  • Darren J. Kelly
  • Christopher Reid
  • Bernard Flynn
  • Danny Liew
  • Bing H. Wang
Review
  • 35 Downloads

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.

Keywords

Adipocyte Aging Airway hypersensitivity Apoptosis Autophagy Cancer Cardiomyopathy Ceramide Ceramide synthase Dihydroceramide desaturase 1-Des-1 Diabetes Dihydrosphinganine FB1 toxicity Hypoxia Neurodegenerative Sphingosine kinase Serine palmitoyl transferase Sphingosine-1-phosphate—S1P Sphingosine-1-phosphate receptors 4-HRP fenretinide 

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

Notes

Author 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.

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.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Ruth. R. Magaye
    • 1
  • Feby Savira
    • 1
  • Yue Hua
    • 1
  • Darren J. Kelly
    • 2
  • Christopher Reid
    • 1
  • Bernard Flynn
    • 3
  • Danny Liew
    • 1
  • Bing H. Wang
    • 1
  1. 1.Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive MedicineMonash UniversityMelbourneAustralia
  2. 2.Department of Medicine, St Vincent’s HospitalUniversity of MelbourneFitzroyAustralia
  3. 3.Australian Translational Medicinal Chemistry Facility, Medicinal Chemistry, Monash Institute of Pharmaceutical SciencesMonash UniversityMelbourneAustralia

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