Implication of Sphingosine-1-P/Sphingosine Kinase Pathway in Non-alcoholic Fatty Liver Disease
Amira M Badr1,2, Yieldez A Bassiouni1,3 and Iman Alqarni1
1Department of Pharmacology and Toxicology, King Saud University, Saudi Arabia
2Department of Pharmacology and Toxicology, Ain Shams University, Egypt
3Department of Clinical Pharmacology, Alexandria University, Egypt
Submission: May 07, 2019; Published: May 31, 2019
*Corresponding author:Amira Badr, Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, 11459 Riyadh, Saudi Arabia
How to cite this article: Amira M Badr, Yieldez A Bassiouni, Iman Alqarni. Implication of Sphingosine-1-P/Sphingosine Kinase Pathway in Non-alcoholic
002 Fatty Liver Disease. Adv Res Gastroentero Hepatol. 2019; 13(1): 555855. DOI: 10.19080/ARGH.2019.13.555855.
Non-alcoholic fatty liver disease (NAFLD) is by far the most common cause of chronic liver diseases and is recently increasing in parallel with the epidemics of obesity and type II diabetes melitus . Recent evidence has emerged of the possible implication of Sphingosine-1-P/Sphingosine Kinase Pathway in NAFLD. Thus, better understanding and modulation of this pathway may play a potential role in the management of NAFLD.
Human non-alcoholic fatty liver disease (NAFLD) is complex where multiple factors acting in parallel in genetically predisposed individuals lead to the development and progression of the disease. Imbalanced lipid metabolism and insulin resistance (IR) are considered as the “first hit, subsequently, the liver becomes vulnerable to other hits involving adipocytokine imbalance, mitochondrial dysfunction, gut-derived bacterial endotoxemia and release of pro-inflammatory and pro-fibrogenic mediators from the impaired organelles [1,2].
Sphingosine1-phosphate (S1P) is a potent bioactive sphingolipid metabolite that regulates diverse cellular processes that are important for inflammation and immune responses. S1P is generated by sphingosine kinases (SphK) 1 and/or 2 from sphingosine which is an intermediate of the ceramide metabolism . Extracellular S1P binds to five high-affinity G protein-coupled receptors (S1PR) with subsequent generation of multiple downstream signals that play essential roles in cell proliferation, differentiation, angiogenesis, inflammation and malignant transformation .
Numerous agonists activate SphK1, including growth factors, hormones, pro-inflammatory cytokines and lipopolysaccharides. SphK1 and S1P are necessary for the phosphorylation of IkBα and nuclear factor-kB (NFκB) activation, Figure 1. Impairment of SphK1/S1P signaling pathway may be a risk factor for impaired insulin signalling which in turn results in over-production and secretion of triglycerides (TG), total cholesterol (C) and very low density lipoprotein by the liver of high fructose-fed hamsters  and rats . Deletion of S1P-lyase which catalyses the irreversible degradation of S1P increases the levels of S1P as well as TG, diacyl glycerol and C in murine liver, indicating a role of the sphingolipid pathway in general lipid metabolism .
Researchers have reported 2-folds elevation of SphK1 in livers
of NAFLD patients . Of importance, Wang et al. investigated the
role of hepatic SphK1/S1P signaling pathway in high fructose-fed
rats and reported that fructose feeding induced hyperlipidemia,
activated SphK1/S1P signaling pathway, elevated SphK1 activity
and S1P production which in turn activated NFκB signaling with
subsequent production of interleucin (IL)-1, IL6 and TNFα leading
to liver inflammation . Also, it was found that overexpression of
exogenous acid sphingomyelinase which catalyses the breakdown
of sphingomyelin to ceramide in mice resulted in hepatic steatosis,
which was blocked by SphK1 deletion, suggesting a pro-steatotic
role of SphK1 .
Another study revealed that SphK1 was induced both in primary
hepatocytes and in vivo in human non-alcoholic steatohepatitis
(NASH) and in a mouse NASH model under overload of saturated
fatty acids (e.g., conditions which occurs with MetS). The
induction of SphK1 and synthesis of S1P lead to the production of pro-inflammatory cytokines. In isolated hepatocytes, the activated
S1P receptors promoted the activation of NFκB-dependent inflammation
and mediated crosstalk with HSC to activate the pro-fibrotic
programs . Thus, it is believed that increased lipids cannot
lead to steatohepatitis unless inflammatory pathways are activated.
As sphingolipids can activate inflammatory mediators, they
are strongly implicated in the transition of simple benign fatty
liver to the more concerning NASH . Recently, Alqarni et al.
 found that S1P and SPK were upregulated in high fructose fed
rats, and this was associated with increased expression of S1PR1
and S1PR3. The increased expression of S1p/SPK was correlated
with increased expression of NF-kB and Toll-4 (TLR4) receptors,
supporting a cross talk of S1P/SPK pathway and TLR4/NF-kB
pathway. This crosstalk was previously reported in other tissues.
S1P has been shown to enhance the protein kinase required by
TLR-dependent NFκB activation which plays a key role in the onset
of local inflammation , Figure 2. Telmisartan, one of the
drugs used for treatment of NAFLD, mediated its effect partially by
inhibiting of S1P/SPK pathway .
So, collectively dysregulation of S1P/SPK pathway is probably
implicated in development of liver diseases, particularly NAFLD,
and thus, modulation of such pathway can help to mitigate
development and progression of NAFLD .