Human and Murine Serine‐Palmitoyl‐CoA Transferase

Weiß, Bertram; Stoffel, Wilhelm

doi:10.1111/j.1432-1033.1997.00239.x

Cited by 191 publications

(148 citation statements)

References 37 publications

(11 reference statements)

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“…81 SPTLC1 encodes one of the subunits of serine palmitoyltransferase, the key enzyme in sphingolipid biosynthesis. 82 These bioactive lipids are altered with obesity and can regulate inflammatory gene expression in adipocytes. 83 Another target gene, GOT2, encodes glutamic-oxaloacetic transaminase, which functions in the inner mitochondrial membrane and has been shown to play a key role in amino acid metabolism.…”

Section: à5mentioning

confidence: 99%

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Civelek

Pan

et al. 2017

The American Journal of Human Genetics

152

211

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Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 3 10 À8 ) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.

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Section: à5mentioning

confidence: 99%

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Civelek

Pan

et al. 2017

The American Journal of Human Genetics

152

211

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“…Mouse and human LCB1 and LCB2 cDNA homologues have also been cloned (7,8). In mouse, the two mRNAs have the same tissue distribution (lung, kidney Ͼ brain Ͼ cartilage, skin Ͼ heart Ͼ liver Ͼ muscle), and the ratio of the amounts of the two transcripts remains approximately constant in all tissues (8). The tissue distribution of LCB2 mRNA parallels the distribution of SPT activity (9).…”

mentioning

confidence: 99%

“…The lack of SPT activity in a yeast strain defective in LCB1 or LCB2, together with the protein similarity data, suggest that the two genes encode subunits of SPT (6). Mouse and human LCB1 and LCB2 cDNA homologues have also been cloned (7,8). In mouse, the two mRNAs have the same tissue distribution (lung, kidney Ͼ brain Ͼ cartilage, skin Ͼ heart Ͼ liver Ͼ muscle), and the ratio of the amounts of the two transcripts remains approximately constant in all tissues (8).…”

mentioning

confidence: 99%

Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

Hojjati

Zhou

et al. 2005

Journal of Biological Chemistry

266

211

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Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis. We injected 8-week-old apoE-deficient mice with myriocin (0.3 mg/ kg/every other day, intraperitoneal) for 60 days. On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001). Plasma total cholesterol and triglyceride levels demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (42% in root and 36% in en face assays) (p < 0.01). On a high fat diet, myriocin treatment caused marked decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (59, 66, and 81%, respectively) (p < 0.0001), and a marked increase in plasma phosphatidylcholine levels (100%) (p < 0.0001). Total cholesterol and triglyceride demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (39% in root and 37% in en face assays) (p < 0.01). These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties. Thus, inhibition of SPT activity could be an alternative treatment for atherosclerosis.Sphingolipids have many biological functions, including cell membrane formation, signal transduction, and lipid metabolism, and all of these may be related to the development of atherosclerosis. Serine palmitoyl-CoA transferase (SPT) 1 is the rate-limiting enzyme in the biosynthesis of sphingolipids (1). It has long been known that SPT plays an important role in the metabolism of sphingolipids, but its role in other lipid metabolisms and atherosclerosis has not been unequivocally determined. When SPT activity is increased in rat liver (2) and lung (3), sphingolipid formation is likewise increased. The activity of SPT is heightened in the aortas of rabbits fed a high cholesterol diet (4). Two candidate cDNAs for yeast SPT, termed LCB1 and LCB2, have been cloned (5, 6), and the translated sequences indicate that their gene products have a 21% amino acid sequence identity (6). The lack of SPT activity in a yeast strain defective in LCB1 or LCB2, together with the protein similarity data, suggest that the two genes encode subunits of SPT (6). Mouse and human LCB1 and LCB2 cDNA homologues have also been cloned (7,8). In mouse, the two mRNAs have the same tissue distribution (lung, kidney Ͼ brain Ͼ cartilage, skin Ͼ heart Ͼ liver Ͼ muscle), and the ratio of the amounts of the two transcri...

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“…A short time after these latter studies were published , two of us showed that dietary deficiency of Mg , in levels found in Western diets, vastly increased atherosclerotic plaques in rabbits fed high-cholesterol diets, whereas high dietary levels of Mg inhibited plaque formations [15]. SPT is a heterodimer of 53-kDa SPT-1 and 63-kDa SPT 2 subunits [60,61], both of which are bound to the endoplasmic reticulum [62]. An upregulation of SPT activity has been hypothesized to play a role in apoptosis [63], cell death events taking place in atherogenesis [41,42,64 ].…”

Section: Causative Events and Pathways Leading To Inflammationatherogmentioning

confidence: 99%

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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Human and Murine Serine‐Palmitoyl‐CoA Transferase

Cited by 191 publications

References 37 publications

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

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

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