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Spotlight: Ceramide Delivery System

February 26, 2016

In addition to its role in cellular structure, the bioactive sphingolipid, ceramide, has been shown to be important for the regulation of a host of cellular functions including cell growth, proliferation, differentiation, senescence, necrosis, and apoptosis [1]. However, poor aqueous solubility of this molecule makes the efficient exogenous cellular delivery of ceramide difficult, thus presenting a challenge for the study of this molecule within cultured cells [1,2]. Delivery of short chain, non-physiological ceramides is achievable through the use of organic solvent-based delivery systems, primarily those that utilize DMSO [1,2]. However, the use of organic solvents is well-known to adversely affect the viability and the phenotypic characteristics of cells [3-5]. Therefore, a solvent-free ceramide delivery system, which enhances the efficiency of delivery without deleterious effects on cells, would be beneficial in the continued study of the cellular effects of this bioactive molecule. Studies by Lonnfors et al. found that ceramides form stable, fluid bilayers with cholesteryl phosphocholine (CholPC) likely due to the ability of the phosphocholine head group attached to cholesterol to shield both lipid species from unfavorable interactions with water [6]. Continued studies by Sukumaran et al. found that this formulation is more potent than solvent-delivered (DMSO) formulations of C6 ceramide in inhibiting proliferation, inducing apoptosis, and disturbing calcium homeostasis [1]. The formation of fluid bilayers that are enriched in C6 ceramide is thought to prevent “crystallization” of the lipid species into the culture medium and allow for the efficient transfer of monomeric ceramide to cell membranes with enhanced bioavailability [1]. Additionally, the bilayer dispersion does not require organic solvent to be introduced during cell culture, thus eliminating any solvent induced cytotoxic effects [1]. While CholPC may additionally be transferred from the C6 ceramide/CholPC formulation, treatment with CholPC alone or with a cholesterol/CholPC formulation did not have a significant effect on cell proliferation (inhibitory or stimulatory) or on the induction of apoptosis [1]. These results suggest that the potent cellular effects reported were due to the increased availability of C6 ceramide when complexed with CholPC [1]. In a most recent study, these findings have been further extended to include the delivery of long-chain ceramides to cells in culture [2]. The study by Kjellberg, et al. found that C6-, C10-, and C16-ceramides can be complexed with CholPC and introduced into cells [2]. Depending on chain length, the delivered ceramide species exhibited differing rates of uptake and metabolic fates [2]. In these studies, the ceramide delivery system described and now available from Avanti Polar Lipids provides an alternative to solvent-based delivery approaches. C6-, C10-, and/or C16-ceramide in a bilayer with CholPC offers improved bioavailability and may be used to enhance cellular response when delivering ceramides to cells in culture [1,2].

References

  1. P. Sukumaran, M. Lonnfors, O. Langvik, I. Pulli, K. Tornquist, J.P. Slotte, Complexation of c6-ceramide with cholesteryl phosphocholine—a potent solvent-free ceramide delivery formulation for cells in culture, PLoS One 8 (2013) e61290.
  2. M. Kjellberg, M. Lonnfors, J.P. Slotte, P. Mattjus. Metabolic Conversion of Ceramides in HeLa Cells – A Cholesteryl Phosphocholine Delivery Approach, PLoS One 10 (2015) e0143385.
  3. S. Adler, C. Pellizzer, M. Paparella, T. Hartung, S. Bremer, The effects of solvents on embryonic stem cell differentiation, Toxicol. In Vitro 20 (2006) 265–271.
  4. R. Pal, M.K. Mamidi, A.K. Das, R. Bhonde, Diverse effects of dimethyl sulfoxide (DMSO) on the differentiation potential of human embryonic stem cells, Arch. Toxicol. 86 (2012) 651–661.
  5. C. Rodriguez-Burford, D.K. Oelschlager, L.I. Talley, M.N. Barnes, E.E. Partridge, W.E. Grizzle, The use of dimethylsulfoxide as a vehicle in cell culture experiments using ovarian carcinoma cell lines, Biotech. Histochem. 78 (2003) 17–21.
  6. M. Lonnfors, O. Langvik, A. Bjorkbom, J.P. Slotte, Cholesteryl phosphocholine—a study on its interactions with ceramides and other membrane lipids, Langmuir 29 (2013) 2319–2329.