March 2011

Fatty acid-mediated regulation of sphingolipid biosynthesis and its role in lipotoxicity

The elevation of plasma lipids that occurs in obesity, diabetes and the metabolic syndrome causes dysregulation of sphingolipid metabolism through multiple mechanisms.

Lipid-News---AT0311
Mechanisms by which fatty acids regulate sphingolipid biosynthesis. Fatty acids enter the cell primarily through plasma membrane transporters. Esterification to CoA allows their utilization for sphingolipid biosynthesis. Mitochondrial fatty acid metabolism causes oxidative stress, which may promote sphingolipid catabolism to generate ceramide.

The U.S. Centers for Disease Control and Prevention state that more than 30 percent of the U.S. population is obese, which constitutes a significant threat to public health. The deleterious effects of obesity largely occur through the perturbation of endocrine function and whole-body metabolism, one outcome of which is an increase in plasma free fatty acids. FFA provide cells with a rich source of energy, but when their concentrations exceed the cell’s capacity for use or storage, they induce apoptosis, insulin resistance and other dysfunctions collectively referred to as “lipotoxicity”(1) .This occurs through initiating stress responses, regulating transcription and promoting production of bioactive lipids.

Sphingolipid synthesis generates more than 1,000 different molecules, many of which have distinct signaling functions. While the best-characterized sphingolipids are ceramide and sphingosine-1-phosphate, recent studies demonstrate additional roles for other sphingolipids. With the diverse impacts of sphingolipids on cell programs, it is not difficult to see why their aberrant production may contribute to disease processes (2).

How do fatty acids regulate sphingolipid synthesis? The first hint arose from the observation that sphingolipid synthesis depends on concentrations of serine and palmitate, substrates for the first enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (3). This is due to the relatively high Km of the enzyme for these substrates and suggests that increasing FFA would increase cell sphingolipids. Indeed, this is observed in cell culture, rodent obesity models and obese humans. Additionally, our group demonstrated that palmitate treatment increased sphingosine-1-phosphate through escalating expression of the sphingosine kinase 1 gene (4). Moreover, metabolic labeling demonstrated that palmitate generated ceramide through sphingolipid catabolism, which may occur through stress-induced activation of sphingomyelinases (5). Thus, multiple mechanisms contribute to FFA regulation of sphingolipid synthesis.

Many studies in this area have considered FFA en masse; however, recent work reveals distinct actions of specific FFAs. For example, oleate (C18:1) overcomes palmitate-induced outcomes in many experimental settings. We observed that oleate attenuated both palmitate-mediated increase in sphingosine kinase 1 (4) and ceramide. In light of these recent findings, it becomes intriguing that obesity increases plasma saturated FFA, suggesting that not only total FFA but also their relative concentrations regulate cell sphingolipid profiles. This and other areas remain underexplored, including the potential regulation of sphingolipids by FFA import and esterification to CoA by Acyl-CoA synthetases. These routes of investigation present rich opportunities for further discovery.

References

1. Unger, R. H., and Scherer, P. E. (2003) Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol. Metab. 21, 345 – 352.
2. Hannun, Y. A., and Obeid, L. M. (2008) Principles of bioactive lipid signaling: lessons from sphingolipids. Nat. Rev. Mol. Cell. Biol. 9, 139 – 150.
3. Merrill, A. H., Jr., Wang, E., and Mullins, R. E. (1988) Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway. Biochemistry 27, 340 – 345.
4. Hu, W., Bielawski, J., Samad, F., Merrill, A. H., Jr., and Cowart, L. A. (2009) Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity. J. Lipid Res. 50, 1852 – 1862.
5. Clarke, C. J., and Hannun, Y. A. (2006) Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim. Biophys. Acta 1758, 1893 – 1901.

L. Ashley Cowart (cowartl@musc.edu) is an assistant professor of biochemistry and molecular biology at the Medical University of South Carolina and a research health scientist at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina.


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