Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation

Abstract

Chronic inflammation is a common underlying factor in many major metabolic diseases afflicting Western societies. Sphingolipid metabolism is pivotal in the regulation of inflammatory signaling pathways. The regulation of sphingolipid metabolism is in turn influenced by inflammatory pathways. In this review, we provide an overview of sphingolipid metabolism in mammalian cells, including a description of sphingolipid structure, biosynthesis, turnover, and role in inflammatory signaling. Sphingolipid metabolites play distinct and complex roles in inflammatory signaling and will be discussed. We also review studies examining dietary sphingolipids and inflammation, derived from in vitro and rodent models, as well as human clinical trials. Dietary sphingolipids appear to influence inflammation-related chronic diseases through inhibiting intestinal lipid absorption, altering gut microbiota, activation of anti-inflammatory nuclear receptors, and neutralizing responses to inflammatory stimuli. The anti-inflammatory effects observed with consuming dietary sphingolipids are in contrast to the observation that most cellular sphingolipids play roles in augmenting inflammatory signaling. The relationship between dietary sphingolipids and low-grade chronic inflammation in metabolic disorders is complex and appears to depend on sphingolipid structure, digestion, and metabolic state of the organism. Further research is necessary to confirm the reported anti-inflammatory effects of dietary sphingolipids and delineate their impacts on endogenous sphingolipid metabolism.

Keywords: atherosclerosis; ceramide; diabetes; inflammation; macrophage; obesity; sphingolipids; sphingomyelin; sphingosine.

Figure 1

Sphingolipid metabolic pathways and enzymes described in mammalian cells. Serine and palmityl-CoA will be utilized to synthesize 3-ketodihydrosphinganine generating the sphingoid backbone (blue). The subsequent dehydrogenation and acylation will produce dihydroceramide which contains a fatty amide (green). Dihydroceramide can be desaturated to produce ceramide. Ceramide can either be used for catabolism to generate sphingosine and sphingosine-1-phosphate or one of many complex sphingolipids with an additional head group (purple). All synthesis reactions producing complex sphingolipids are reversible, while the sphingosine-1-phosphate catabolic reaction is not. Abbreviations: Cer1PP, ceramide-1-phosphate phosphatase; Cerases, acid-, alkaline-, and neutral-ceramidase; CerK, ceramide kinase; CerS1-6, ceramide synthase 1-6; DHCD1, dihydroceramide desaturase 1; GalCerase, galactosylceramidase; GluCerase, glucosylceramidase; KDSR, ketodihydrosphingosine reductase; LacCS, lactosylceramide synthase; S1PL: sphingosine-1-phosphate lyase; S1PP: sphingosine-1-phosphate phosphatase; SMases, acid-, alkaline-, and neutral-sphingomyelinase; SMS1/2, sphingomyelin synthase 1/2; SPK, sphingosine kinase; SPT, serine palmitoyltransferase; UGalCGT, UDP-galactose-ceramide galactosyltransferase; UGluCGT, UDP-glucose-ceramide glucosyltransferase.

Figure 2

Potential effects of dietary sphingolipids relevant to acute and/or chronic inflammation. Abbreviations: GluCer, glucosylceramide; LPS, lipopolysaccharide; SM, sphingomyelin; ↑, increase; ↓ decrease.