Sphingolipid homeostasis in the web of metabolic routes

Aguilera-Romero, Auxiliadora; Gehin, Charlotte; Riezman, Howard

doi:10.1016/j.bbalip.2013.10.014

Cited by 76 publications

(42 citation statements)

References 147 publications

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“…1 Sphingolipid metabolites are also important signaling molecules linked to multiple other metabolic pathways with kinases and phosphatases as regulatory targets. 2,3 Sphingolipids have roles in numerous cell processes, including regulation of mitochondrial function, cell death and aging. 2,4 Cellular sphingolipid homeostasis is maintained by control of synthesis, breakdown and interorganellar transport of sphingolipid metabolites.…”

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confidence: 99%

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

et al. 2017

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Sphingolipids are structural components of cell membranes that have signaling roles to regulate many activities, including mitochondrial function and cell death. Sphingolipid metabolism is integrated with numerous metabolic networks, and dysregulated sphingolipid metabolism is associated with disease. Here, we describe a monogenic yeast model for sphingolipid accumulation. A csg2Δ mutant cannot readily metabolize and accumulates the complex sphingolipid inositol phosphorylceramide (IPC). In these cells, aberrant activation of Ras GTPase is IPC-dependent, and accompanied by increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial mass. Survival or death of csg2Δ cells depends on nutritional status. Abnormal Ras activation in csg2Δ cells is associated with impaired Snf1/AMPK protein kinase, a key regulator of energy homeostasis. csg2Δ cells are rescued from ROS production and death by overexpression of mitochondrial catalase Cta1, abrogation of Ras hyperactivity or genetic activation of Snf1/AMPK. These results suggest that sphingolipid dysregulation compromises metabolic integrity via Ras and Snf1/AMPK pathways.Sphingolipids are critical structural molecules in cell membranes, forming membrane microdomains by associating with cholesterol and specific proteins.1 Sphingolipid metabolites are also important signaling molecules linked to multiple other metabolic pathways with kinases and phosphatases as regulatory targets.2,3 Sphingolipids have roles in numerous cell processes, including regulation of mitochondrial function, cell death and aging.2,4 Cellular sphingolipid homeostasis is maintained by control of synthesis, breakdown and interorganellar transport of sphingolipid metabolites.1 The importance of sphingolipids is underscored by several lysosomal storage disorders, including Tay Sachs, Gaucher and Nieman-Pick diseases, which are attributable to defective sphingolipid breakdown; similarly, a hereditary sensory neuropathy is caused by accumulation of abnormal sphingolipid metabolites.

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confidence: 99%

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

et al. 2017

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“…Altogether, we propose that the reduced delivery of a less-active SI to the microvillus membrane in the patient's enterocytes elicits carbohydrate malabsorption and appearance of GI symptoms in the NPC patient. In biological membranes, cholesterol and sphingolipids are often associated with each other, and it has been suggested that metabolism of either one of these lipids in different LSDs results in an impaired localization and function of both of them (Aguilera-Romero et al 2014). NPC disease offers a support to this view, since the impaired cholesterol transport due to mutations in the NPC1 gene leads to accumulation of cholesterol and subsequently sphingolipids in late endosomes and lysosomes (Parkinson-Lawrence et al 2010).…”

Section: Resultsmentioning

confidence: 99%

The Pathobiochemistry of Gastrointestinal Symptoms in a Patient with Niemann-Pick Type C Disease

Amiri¹,

Kuech²,

Shammas³

et al. 2015

JIMD Reports

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The molecular basis of gastrointestinal intolerances in a severe case of Niemann-Pick type C disease was analyzed in an intestinal biopsy specimen. The enzyme activities of intestinal sucrase-isomaltase and maltaseglucoamylase are reduced in the patient, while that of lactase is comparable to the control. The association of SI with lipid rafts is reduced in the patient's biopsy as a consequence of altered composition of membrane microdomains. As association with lipid rafts influences the intracellular transport and the enzyme activities of sucraseisomaltase and maltase-glucoamylase, these data explain reduced carbohydrate digestion in the intestinal lumen and delineate the effect of deficient cholesterol and sphingolipid homeostasis in development of gastrointestinal symptoms in NPC patients.

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“…It has been shown by our group [4,25,43,51] and others [52][53][54] that ceramides, in increased levels, found in the atherogenic process[mixed in plaques; unpublished findings ], at least in rabbits, and stimulated in MgD states could be important causal and initiating agents [16,17].…”

Section: Causative Events and Pathways Leading To Inflammationatherogmentioning

confidence: 99%

“…We have recently demonstrated that cerebral, aortic and coronary VSM cells can also elaborate and release PAF [69]. There are some reports that both PAF and ceramides may result in transformation of VSM cells from one phenotype to another, as is typical in the atherosclerotic process [53,54,72,73]. In addition, like we see in MgD, PAF produces vasoconstriction of blood vessels and a variety of VSM types [for recent review, see 69], as do several of the ceramides [69,74,75].…”

Section: Is the Mysterious Intermediary Molecule Possibly Related To mentioning

confidence: 99%

“…Ceramides are now thought to play important roles in fundamental processes such as inflammation, angiogenesis, membrane-receptor functions, cell proliferation, microcirculatory functions, cell adhesion, immunogenic responses, excitation-coupling events in smooth muscles, and cell death(i.e., apoptosis) [52][53][54][55][56][57]. SPT 1 and SPT 2 are the rate-limiting enzymes in the biosynthesis of sphingolipids [58].…”

Section: Causative Events and Pathways Leading To Inflammationatherogmentioning

confidence: 99%

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Potential Roles of Magnesium Deficiency in Inflammation and Atherogenesis: Importance and Cross-talk of Platelet-Activating Factor and Ceramide

Bm¹

2016

J Clin Exp Cardiolog

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Epidemiologic studies in North America and Europe have shown that people consuming Western-type diets are low in magnesium (Mg) content (i.e., < 30 -65% of the RDA for Mg); most such diets in the USA show that 60 -80% of Americans are consuming only 185 -235 mg/day of Mg. Low Mg content in areas of soft-water, and Mg-poor soil, is associated with high incidences of ischemic heart disease (IHD), coronary artery disease, hypertension, and sudden cardiac death (SCD). It is clear that the leading underlying cause of death worldwide is atherosclerosis. Importantly, both animal and human studies have shown an inverse relationship between dietary intake of Mg and atherosclerosis. The myocardial level of Mg has consistently been observed to be lower in subjects dying from IHD and SCD in soft-water areas than those in hard-water areas. Over the past 20 years, our laboratories, using several types of primary cultured vascular smooth muscle (VSM) cells, and myocardial cells, demonstrated that declining levels of extracellular Mg ([Mg 2+ ] 0 ) activated several enzymatic pathways to produce increases in cellular sphingolipids, particularly ceramides which are known to exert numerous types of cardiovascular manifestations including inflammatory effects ; the latter play important roles in atherogenesis and cardiovascular diseases. Approximately 20 years ago, we reported that low [Mg 2+ ] 0 caused formation of platelet-activating factor (PAF) as well as other types of PAF-like molecules and suggested that these molecules might be causative agents in low Mg 2+ -induced IHD and SCD. Herein, we review results and data from our labs which strongly support roles for ceramides, PAF and PAF-like lipids in low [Mg 2+ ] 0 -induced IHD and SCD.

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Sphingolipid homeostasis in the web of metabolic routes

Cited by 76 publications

References 147 publications

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

The Pathobiochemistry of Gastrointestinal Symptoms in a Patient with Niemann-Pick Type C Disease

Potential Roles of Magnesium Deficiency in Inflammation and Atherogenesis: Importance and Cross-talk of Platelet-Activating Factor and Ceramide

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