BACKGROUND: Sphingolipids (SPs) are ubiquitous, structurally diverse molecules that include ceramides, sphingomyelins (SMs), and sphingosines. They are involved in various pathologies, including obesity and type 2 diabetes mellitus (T2DM). Therefore, it is likely that perturbations in plasma concentrations of SPs are associated with disease. Identifying these associations may reveal useful biomarkers or provide insight into disease processes. METHODS: We performed a lipidomics evaluation of molecularly distinct SPs in the plasma of 2302 ethnically Chinese Singaporeans using electrospray ionization mass spectrometry coupled with liquid chromatography. SP profiles were compared to clinical and biochemical characteristics, and subjects were evaluated with follow-up visits for 11 years. RESULTS: We found that ceramides correlated positively but hexosylceramides correlated negatively with BMI and homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, SPs with a d16:1 sphingoid backbone correlated more positively with BMI and HOMA-IR, while d18:2 SPs correlated less positively, relative to canonical d18:1 SPs. We also found that higher concentrations of 2 distinct SMs were associated with a higher risk of T2DM (HR 1.45 with 95% CI 1.18–1.78 for SM d16:1/18:0 and HR 1.40 with 95% CI 1.17–1.68 for SM d18:1/18:0). CONCLUSIONS: We identified significant associations between SPs and obesity/T2DM characteristics, specifically, those of hexosylceramides, d16:1 SPs, and d18:2 SPs. This suggests that the balance of SP metabolism, rather than ceramide accumulation, is associated with the pathology of obesity. We further identified 2 specific SPs that may represent prognostic biomarkers for T2DM. FUNDING: National University Health System (NUHSRO/2014/085/AF-Partner/01) and the National Research Foundation Investigatorship grant (NRF-NRFI2015-05).

Ototoxicity is a major adverse effect of platinum-based chemotherapeutics and currently, there remains a lack of United States Food and Drug Administration-approved therapies to prevent or treat this problem. In our study, we examined the role of the sphingosine 1-phosphate receptor 2 (S1P₂) in attenuating cisplatin-induced ototoxicity in several different animal models and cell lines. We found that ototoxicity in S1P₂ knockout mice is dependent on reactive oxygen species (ROS) production and that S1P₂ receptor activation with a specific agonist, CYM-5478, significantly attenuates cisplatin-induced defects, including hair cell degeneration in zebrafish and prolonged auditory brainstem response latency in rats. We also evaluated the cytoprotective effect of CYM-5478 across different cell lines and showed that CYM-5478 protects neural-derived cell lines but not breast cancer cells against cisplatin toxicity. We show that this selective protection of CYM-5478 is due to its differential effects on key regulators of apoptosis between neural cells and breast cancer cells. Overall, our study suggests that targeting the S1P₂ receptor represents a promising therapeutic approach for the treatment of cisplatin-induced ototoxicity in cancer patients.

Sphingolipid concentrations have been associated with risk of type 2 diabetes and cardiovascular diseases. Because sphingolipids can be synthesized de novo from saturated fatty acids (SFA), dietary fatty acids may affect plasma sphingolipid concentrations. We aimed to evaluate dietary fat and protein intakes in relation to circulating sphingolipid levels. We used cross-sectional data from 2860 ethnic Chinese Singaporeans collected from 2004–2007. Nutrient intakes were estimated on the basis of a validated 159-item food frequency questionnaire. We quantified 79 molecularly distinct sphingolipids in a large-scale lipidomic evaluation from plasma samples. Higher saturated fat intake was associated with higher concentrations of 16:1; O2 sphingolipids including ceramides, monohexosylcermides, dihexosylceramides, sphingomyelins, and sphingosine 1-phosphates. Higher polyunsaturated fat intake was associated with lower plasma long-chain ceramides and long-chain monohexosylcermide concentrations. Protein intake was inversely associated with concentrations of most subclasses of sphingolipids, with the exception of sphingolipids containing a 16:1; O2 sphingoid base. Lower intake of saturated fat and higher intake of polyunsaturated fat and protein may decrease plasma concentrations of several sphingolipid classes. These findings may represent a novel biological mechanism for the impact of nutrient intakes on cardio-metabolic health. This work was supported by the National Research Foundation Investigatorship grant (NRF-NRFI2015–05, to MRW), A^*STAR (I1901E0040), and the National University Health System (NUHSRO/2014/085/AF-Partner/01, DRH). FT was supported by the NRF and A^*STAR IAF-ICP I1901E0040.