Unsaturated Fatty Acid-mediated Decreases in Sterol Regulatory Element-mediated Gene Transcription Are Linked to Cellular Sphingolipid Metabolism

Worgall, Tilla S.; Johnson, Rebecca A.; Seo, Toru; Gierens, H.; Deckelbaum, Richard J.

doi:10.1074/jbc.m102393200

Cited by 96 publications

(63 citation statements)

References 58 publications

(61 reference statements)

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“…Other reports in the literature demonstrate that phospholipids can act as intracellular chaperones for proteins (43). It has also been shown that fatty acids influence cellular phospholipid metabolism (15,44), and this could impact either the composition or the amount of phospholipid associated with apoE in intracellular membranes, thereby altering its conformation, its availability to be a substrate for post-translational glycosylation, and its retention time in the Golgi. Third, we have previously shown that newly synthesized apoE is retained in a cell surface pool and can be recycled to the Golgi where additional sialic acid residues are added prior to secretion (32).…”

Section: Resultsmentioning

confidence: 99%

Oleic Acid Modulates the Post-translational Glycosylation of Macrophage ApoE to Increase Its Secretion

Huang

Mazzone

2004

Journal of Biological Chemistry

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There has been increasing interest in a potential role for fatty acids in adversely affecting organismal substrate utilization and contributing to the cardiovascular complications in insulin resistance. Fatty acids have already been implicated in regulating the expression of a number of genes in resident cells of the vessel wall. In the current studies, we evaluated a potential role for fatty acids in the regulation of macrophage apoE expression. Incubation in oleic acid increased the synthesis and secretion of apoE by human monocyte-derived macrophages. Part of this stimulation was mediated at a posttranslational locus. Oleic acid increased the secretion of apoE from macrophages that constitutively expressed a human apoE3 cDNA. Incubation in palmitic acid decreased apoE secretion from these cells. The effect of oleic acid on apoE secretion could not be accounted for by the known effect of fatty acid on cellular sterol, because incubation in oleic acid did not suppress the degradation of nascent apoE. Incubation in oleic acid for at least 6 h was required to observe an effect on apoE secretion. Oleic acid altered the glycosylation pattern of cellular and secreted apoE, with a loss of the most heavily sialylated isoform. Oleic acid had no effect on the glycosylation of interleukin 6 secreted from macrophages. Elimination of apoE glycosylation, by substitution of threonine 194 with alanine, eliminated oleic acid-mediated stimulation of apoE secretion. These results indicate that oleic acid increases apoE secretion from macrophages at a locus involving post-translational glycosylation.

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Section: Resultsmentioning

confidence: 99%

Oleic Acid Modulates the Post-translational Glycosylation of Macrophage ApoE to Increase Its Secretion

Huang

Mazzone

2004

Journal of Biological Chemistry

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“…Total and C18:0 serum dihydroceramide and ceramide have been shown to be associated with prediabetes and diabetes (8,15,28) as well as able to predict progression to type 2 diabetes in epidemiological cohorts (26,28). Recent data indicate that dihydroceramide is more than an inactive precursor to ceramide formation and is an important intra-and extracellular signal influencing sterol regulatory element gene transcription, autophagy, and mitochondrial function (3,32,36,38). Although more work is needed, our data are consistent with serum dihydroceramide impacting insulin sensitivity in humans.…”

Section: Discussionmentioning

confidence: 99%

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Bergman

Brozinick

Strauss

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

127

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Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% V O2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurancetrained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1-phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-B activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future. insulin sensitivity; athlete's paradox; lipid composition; plasma biomarkers THE GLOBAL BURDEN OF DIABETES continues to rise, fueled by the even greater epidemic of prediabetes (9). Nevertheless, not all of those with prediabetes will develop diabetes (27), highlighting the need to identify nonglycemic markers of disease progression that may also prove useful as new targets for the treatment of diabetes itself. Advances in lipidomics have provided new tools to investigate processes that govern the development of diabetes and its complications beyond that of glucose itself. Serum ceramides, a family of sphingolipids involved in diverse and relevant metabolic processes, have received considerable attention in relation to diabetes, making them prime candidates for further examination. Unlike other biomarkers, discrete serum ceramide profiles are rendered across the spectrum of diabetogenesis, creating speculation that ceramides not only mark but contribute to the disease process (8, 17).Much of this speculation is derived from data generated from in vitro and animal experimentation. Human data to date are limited largely to associations between serum ceramide concentration and risk for both diabetes (15) and related comp...

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“…Several in vitro studies have shown that oleate suppresses the proteolytic processing of SREBP-1 protein and reduces SREBP-1 and lipogenic gene expression (52)(53)(54). The inhibitory effect has been proposed to be attributed to the increase in the release of ceramide from sphingomyelin (55). The opposite effect between in vitro and in vivo results is a common feature in the studies of nutrient-gene interaction.…”

Section: Discussionmentioning

confidence: 99%

Stearoyl-CoA Desaturase 1 Gene Expression Is Necessary for Fructose-mediated Induction of Lipogenic Gene Expression by Sterol Regulatory Element-binding Protein-1c-dependent and -independent Mechanisms

Miyazaki

Dobrzyń²,

Man³

et al. 2004

Journal of Biological Chemistry

260

215

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Stearoyl-CoA desaturase (SCD) synthesizes oleate necessary for the biosynthesis of triglycerides and other lipids. Mice with a targeted disruption of the SCD1 gene are deficient in tissue oleate and have reduced expression of the sterol regulatory element-binding protein (SREBP) and its target genes. The SREBP-1c isoform is a known mediator of insulin action on hepatic gene expression, but its transcriptional effects due to glucose or fructose are still unclear. We found that fructose compared with glucose is a stronger inducer of SREBP-1c and lipogenic gene expression, causing a dramatic increase in hepatic triglyceride levels. However, when fed to the SCD1؊/؊ mice, fructose failed to induce SREBP-1 or lipogenic genes and the triglyceride levels were not increased. Instead fructose feeding caused a decrease in hepatic glycogen and plasma glucose levels. The induction of SREBP-1 and lipogenic gene expression as well as the levels of liver triglycerides, glycogen, and plasma glucose was partially restored when the fructose diet was supplemented with very high levels of oleate (20% by weight) but not with palmitate, stearate, or linoleate. Fructose in a long term feeding induced the expression of SCD1 and that of other lipogenic genes in the liver of SREBP-1c؊/؊ mice, and a further increase in expression of these genes occurred when the fructose diet was supplemented with oleate. Our observations demonstrated that oleate produced by SCD is necessary for fructosemediated induction of lipogenic gene expression through SREBP-1c-dependent and -independent mechanisms and suggested that SCD1 gene expression is important in lipid and carbohydrate homeostasis.

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Unsaturated Fatty Acid-mediated Decreases in Sterol Regulatory Element-mediated Gene Transcription Are Linked to Cellular Sphingolipid Metabolism

Cited by 96 publications

References 58 publications

Oleic Acid Modulates the Post-translational Glycosylation of Macrophage ApoE to Increase Its Secretion

Oleic Acid Modulates the Post-translational Glycosylation of Macrophage ApoE to Increase Its Secretion

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Stearoyl-CoA Desaturase 1 Gene Expression Is Necessary for Fructose-mediated Induction of Lipogenic Gene Expression by Sterol Regulatory Element-binding Protein-1c-dependent and -independent Mechanisms

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