Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Abstract

The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and/or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyasedeficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern, with a significant increase in the expression of PPAR␥, a master transcriptional regulator of lipid metabolism. However, the mRNA expression of the genes encoding the sphingosine kinases and S1P phosphatases, which directly control the levels of S1P, were not significantly changed in liver of the S1P lyase-deficient mice. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases.Sphingolipid metabolism generates diverse lipid molecules that are utilized by cells in multiple ways (Fig. 1A) (1, 2). Complex sphingolipids, such as sphingomyelin and glycosphingolipids, are structural components of cell membranes and drive the formation of plasma membrane lipid domains by virtue of their interactions with sterols. Metabolic intermediates, notably sphingosine, ceramide, and sphingosine-1-phosphate (S1P), 3 serve as bioactive molecules by regulating cellular signaling pathways. An additional function of sphingolipid metabolism is the synthesis of substrates that are utilized by other lipid metabolic hubs. However, the functional, regulatory, and physiological significance of the intersection of sphingolipid metabolism with other lipid pathways is not well understood.A decisive step in the sphingolipid metabolic pathway is carried out by S1P lyase, encoded by the Sgpl1 gene (3, 4). S1P lyase, which resides in the endoplasmic reticulum and is widely distributed in tissues, catalyzes the final degradative step in the sphingolipid metabolic pathway with the cleavage of phosphorylated sphingoid bases to generate phosphoethanolamine and a fatty aldehyd...

Identification of acyl-CoA synthetases involved in the mammalian sphingosine 1-phosphate metabolic pathway

“…4B) via FA elongation. We also subjected half of the FAME products to double-bond cleavage assays 14 using KIO 4 and KMnO 4 , where carbon-carbon double bonds undergo oxidation to form two carboxylic acids [17]. As expected, saturated C16:0-ME and C18:0-ME were resistant to the KIO 4 /KMnO 4 treatment, whereas double bond-containing cis-9-C16:1-ME was cleaved to nonanedioic acid ME (NA-ME in Fig.…”

“…Since the S1P metabolic pathway is the sole pathway allowing conversion of the LCB portion of sphingolipids to acyl-CoAs and further to glycerophospholipids, its failure to function may lead to aberrant sphingolipid homeostasis. Indeed, knockout mice for the Spl (Sgpl1) gene, which encodes S1P lyase that catalyzes the first, irreversible step of the S1P metabolic pathway, have a pleiotropic phenotype, including abnormal lipid homeostasis in the liver, brain, and adipose tissue, myeloid cell hyperplasia, skeletal and hematological dysfunctions, and lesions in the lung, heart, urinary tract, and bone, and these mice die approximately one month after birth [4,5].…”

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…The turnover and degradation of sphingolipids is likely to play a key role in sphingolipid homeostasis, as evidenced by the accumulation of sphingolipids that occurs in lysosomal storage diseases or in mice lacking the lyase enzyme (Bektas et al 2010;Schulze and Sandhoff 2011). Additionally, a hereditary sensory neuropathy was recently shown to be owing to mutations in SPT that cause the aberrant production of sphingolipids that cannot be degraded by the lyase.…”

Sphingosine 1-Phosphate (S1P) Lyase Deficiency Increases Sphingolipid Formation via Recycling at the Expense of de Novo Biosynthesis in Neurons

“…In addition, life expectancy of these mice is generally reduced to 6 -8 weeks. Their reduced body weight (to about half of their age-matched littermates) is accompanied by the complete absence of adipose tissue (8). However, the amount of lipids including sphingolipids and cholesterol is considerably elevated in serum and liver of these mice (8).…”