Review
Metabolism of sphingolipids in the gut and its relation to inflammation and cancer development

https://doi.org/10.1016/j.plipres.2008.04.003Get rights and content

Abstract

Sphingolipids are abundant in the microvillar membrane of intestinal epithelial cells where they are essential for structural integrity and may act as receptors for toxins, virus and bacteria. Metabolism of dietary and membrane sphingolipids in the intestine generates ceramide, sphingosine, sphingosine-1-phosphate, and ceramide-1-phosphate, via the action of alkaline sphingomyelinase, neutral ceramidase, sphingosine-1-kinase, and ceramide-1-kinase. These intermediary metabolites act as bioactive lipid messengers, influencing numerous cellular functions including growth, differentiation and apoptosis of both epithelial and immunocompetent cells in the gastrointestinal tract, and also the progress of inflammation and responsiveness of the mucosal cells to pathogens. This review summarizes background and recent progress in the metabolism of dietary and endogenous sphingolipids in the gut and its pathophysiological implications.

Introduction

The interest in sphingolipids is increasing. A number of recent reviews have covered broad perspectives on sphingolipids, including metabolism [1], [2], absorption and transport [3], roles in signaling pathways [4], [5], [6], [7], [8], enzymes involved [9], [10], [11], and relation to tumorigenesis [12] and inflammation [13]. Among the biologically active sphingolipid metabolites, ceramide and sphingosine-1-phosphate (S1P) are considered most important. Ceramide is a major lipid messenger that inhibits cell proliferation and induces apoptosis via dephosphorylation and inactivation of several proliferative and antiapoptotic molecules such as Akt, Bcl-2, PKCα and pRB. It also activates several kinases as Raf kinase and JNK depending on cell types [10], [14], [15]. S1P functions as a second messenger inside the cells, and as an extracellular signal via G-protein coupled receptors [5], [16]. Increasing evidence indicates important roles of S1P in regulation of cell growth, angiogenesis, immune function and lymphocyte traffic, affecting downstream signaling molecules such as PLC, PI3K, Akt, VEGF, and COX 2 [16], [17], [18]. Recent studies have indicated that ceramide-1-phosphate (C1P) is also an important lipid signal that affects cell proliferation and inflammation through activation of PLA2 [19], [20] (Fig. 1).

Sphingolipids, in particular glucosylceramide, are abundant in the apical membrane in the absorptive epithelium in the gut, and are considered important for the preservation of structural integrity during exposure to bile salts and enzymes [21]. The brush border sphingolipids may also support the insertion of transporters and receptors, necessary for the selective and effective transport of nutrients into the cells, although these aspects are poorly characterized. Sphingolipid composition changes when crypt cells differentiate to mature absorptive cells, reflecting the close connection between sphingolipid synthesis and mucosal regeneration and differentiation.

Hydrolytic ectoenzymes, including those digesting sphingolipids, account for an important part of the proteins of the brush border [21]. Sphingolipid metabolites may thus be generated both by intracellular enzymes occurring in most cell types and by ectoenzymes acting on sphingolipids in the diet and in the outer leaflet of the absorptive cells. The generated ceramide, sphingosine, and S1P are intermediates in the conversion of sphingoid bases to chylomicron palmitic acid or in sphingolipid synthesis; they may reach signaling targets and act as messengers [3].

The relation of the sphingolipids in the gut to intestinal inflammation and colorectal cancer (CRC) is a novel and complex issue. Both CRC and inflammatory bowel diseases (IBD) are common diseases that result from gene - environmental interactions including a dietary influence. Current hypotheses for IBD pathogenesis emphasize a deregulation of the normal inflammatory response to the commensal bacterial flora [22]. Studies on gene targeted animals and in patients indicate that deregulation originating from defect barrier integrity, or from innate or specific immunity, may result in similar phenotypes [23]. Lipid signaling via eicosanoids, glycerolipid- and sphingolipid messengers is an important feature of IBD [24]. Most CRCs involves a stepwise series of mutations resulting in a progression to benign adenomas and eventually CRC, which can long be influenced by diet and drugs [25], [26]. The role of lipid messengers is highlighted by the protective effect of cyclooxygenase inhibitors (NSAID, non steroid anti-inflammatory drugs) against CRC development [27] and by the fact that the same types of the drugs make ulcerative colitis worse [28].

This review focuses on the metabolism of sphingolipids in the gastrointestinal tract and the potential relation to mucosal protection, inflammation and carcinogenesis. Since the exposure to exogenous sphingolipids and the enzymes involved are unique features of the gastrointestinal tract, these aspects are covered in some detail.

Section snippets

Sphingolipid profile in the intestinal tract

Throughout the gastrointestinal tract sphingolipids are enriched in the apical membrane of the polarized epithelial cells. The sphingolipid profiles have been characterized by TLC, GLC and GLC–MS techniques with regard to sphingoid base, fatty acid and polar head group composition.

The stomach mucosa contains neutral glycolipid species with one, two, three or five sugars [29], acidic glycolipids of the sulphatide and ganglioside classes, and more complex neutral glycolipids with blood group

Synthesis and degradation of sphingolipids in the gut

The differentiation and turnover of mucosal cells in the gastrointestinal tract are rapid. During the process, glyco-SLs and SM must be synthesized and degraded accordingly. Furthermore 6–10% of the polar lipids in chylomicrons secreted into chyle are SM. The need of sphingolipids for mucosal renewal and lipoprotein secretion is difficult to estimate precisely, but may be of the order 1.5 g per day in humans [3]. Since there is no evidence for any substantial uptake of plasma lipoprotein

Intestinal sphingolipids and inflammatory bowel diseases

Inflammatory bowel disease (IBD), primarily Crohn’s disease and ulcerative colitis, are common diseases caused by an interaction between genetic predisposition and environmental factors. An excess of polymorphonuclear leukocytes, eosinophils, macrophages and different subtypes of B- and T-lymphocytes are present in varying proportions and with different tissue location depending on the type and stage of disease. At the site of inflammation, cytokines, eicosanoids and glycerolipid- and

Link of sphingolipid metabolism with colonic tumorigenesis

Since ceramide and sphingosine are regulators of cell growth, differentiation and apoptosis, the questions have been asked whether the metabolites formed from dietary or membrane SM may influence the cell cycle of the gut epithelium under normal and tumorigenic conditions, and whether sphingolipid metabolites regulate normal proliferation and differentiation in crypt cell progenitor compartment and cell fate along the crypt villous axis. Analytical studies more than two decades ago identified

Future perspectives

Sphingolipids are both cellular constituents and dietary components. The intestinal tract is an organ that is rich in sphingolipids. Today important features have emerged from studies of the sphingolipid rich interface and of the metabolism and anticancer effects of dietary sphingolipids. New information has been gained which make S1P a potential target in the treatment of colorectal cancer and IBD. An immense complexity remains, however, to be structured. Sphingolipid digestion is an extended

Acknowledgements

Original work in the laboratory of the authors were supported by the Swedish Cancer Society, the Swedish Research Council, Formas (Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning), the Albert Påhlsson Foundation, and Research Funds of Lund University Hospital.

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