The role of dihydrosphingolipids in disease

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

Fig. 1

De novo sphingolipid biosynthesis pathway. In the de novo pathway, the condensation of palmitoyl-CoA and serine by the enzyme SPT forms 3-ketoSph. This is then reduced by 3-KR to dhSph. The acylation and phosphorylation of dhSph by CerS1-6 and SK 1 and 2 leads to the formation of dhCer and dhS1P, respectively. Des-1 and -2 then catalyze the desaturation of dhCer to Cer, which is a non-reversible reaction. The metabolization of Cer by CDase produces Sph. The production of S1P from Sph is exclusively phosphorylated by SK 1 and 2. S1P is then degraded to ethanolamine phosphate (EAP) and trans-2-hexadecenal by S1P lyase (SPL). DhS1P and S1P can be converted back to dhSph and Sph by S1P phosphatase (S1PP) and dhSph and Sph to dhCer and Cer, respectively, by cDase

Fig. 2

Comparison of C2-ceramide with C2-dihydroceramide, without the double bond

Fig. 3

Possible effects of dhCer on adipocytes. The ablation or inhibition of Des-1 by drugs such as Fen (4-HRP-fenretinide) in adipocytes leads to increased dhCer, (1) reducing adipogenesis and (2) increasing autophagy and resulting in increased insulin sensitivity and glucose uptake. (1) Increased dhCer reduces adipogenesis by (a) causing endoplasmic reticulum (ER) stress or nutrient stress which then phosphorylates eIF2alpha downstream of PERK (Protein Kinase R-like Endoplasmic Reticulum Kinase), resulting in cell cycle arrest at G1, and (b) the increased dhCer also inhibits ligand activation of PPARγ. Both of these lead to reduced differentiation of adipocytes due to reduced expression of cyclins D1, D3 and E and cdk2. (2) DhCer also increases autophagy by reducing mitochondrial respiration and complex IV, which results in reduced ATP synthesis. The impaired ATP synthesis leads to increased AMPK, activating the phosphorylation of ULK1 (unc-51 like Autophagy Activating Kinase 1), Beclin 1 and LC3B II, which are involved in the initiation and formation of autophagomsomes. This leads to increased expression of autophagy genes such as atg7 and E1-like, thus increasing autophagy. An increase in AMPK also increases GLUT4 translocation to the cell membrane, leading to increased glucose uptake. The hypothesis of dhCer acting as a ligand to activate RARα thus inhibiting PPARγ remains to be deciphered (light blue dotted line)

Fig. 4

DhCer in diseases. A summary of the potential effects of increased dhCer as highlighted in this review

Fig. 5

DhS1P in disease. A summary of the potential effects of increased dhS1P as highlighted in this review