The Possible Contribution of a General Glycosphingolipid Transporter, GM2 Activator Protein, to Atherosclerosis

Yanai, Hidekatsu; Yoshida, Hiroshi; Tomono, Yoshiharu; Tada, Norio; Chiba, Hitoshi

doi:10.5551/jat.13.281

Cited by 12 publications

(9 citation statements)

References 37 publications

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“…Gangliosides are degraded in the lysosome, disruption of which contributes to pathological conditions including atherosclerosis (37,38). Gm2 ganglioside is degraded by the enzyme HexB, and atherosclerotic mice exhibit increased serum Gm2 ganglioside (39).…”

Section: Clock Output Regulation Of Metabolism Is Modified In Id2mentioning

confidence: 99%

ID2 (Inhibitor of DNA Binding 2) Is a Rhythmically Expressed Transcriptional Repressor Required for Circadian Clock Output in Mouse Liver

Hou

Ward

Murad

et al. 2009

Journal of Biological Chemistry

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Id2 is a helix-loop-helix transcription factor gene expressed in a circadian manner in multiple tissues with a phase-locked relationship with canonical clock genes (1). Our previous studies have identified circadian phenotypes in Id2 null mice, including enhanced photo-entrainment and disruption of activity rhythms, and have demonstrated a potent inhibitory effect of ID proteins upon CLOCK-BMAL1 transactivation of clock gene and clock-controlled gene activity (1). We have now begun to explore the potential role that ID2 may play in specifically regulating clock output. Here we show that ID2 protein is rhythmically expressed in mouse liver. Time-of-day-specific liver gene expression in Id2 ؉/؉ and Id2 ؊/؊ mice under circadian conditions was studied using DNA microarray analysis, identifying 651 differentially expressed genes, including a subset of 318 genes deemed rhythmically expressed in other studies. Examination of individual time courses reveals that these genes are dysregulated in a highly time-specific manner. A cohort of different functional groups were identified, including genes associated with glucose and lipid metabolism, e.g. serum protein Igfbp1 and lipoprotein lipase. We also reveal that the Id2 ؊/؊ mice show a reduction in lipid storage in the liver and white adipose tissue, suggesting that disruption of normal circadian activity of components of lipid metabolism can result in overt physiological alterations. These data reveal a role for the transcriptional repressor ID2 as a circadian output regulator in the periphery.Circadian rhythms are endogenous biochemical, physiological, and behavioral 24-h oscillations that persist under constant conditions and are generated by a series of intracellular transcriptional-translational feedback loops, composed of positive and negative components (2, 3). The positive loop consists of CLOCK (circadian locomotor output cycle kaput) and BMAL1

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Section: Clock Output Regulation Of Metabolism Is Modified In Id2mentioning

confidence: 99%

ID2 (Inhibitor of DNA Binding 2) Is a Rhythmically Expressed Transcriptional Repressor Required for Circadian Clock Output in Mouse Liver

Hou

Ward

Murad

et al. 2009

Journal of Biological Chemistry

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“…18 This mechanism has been already shown in atherosclerotic lesions, in which ceramide has been demonstrated to stimulate the proliferation of aortic smooth muscle cells. 19 …”

Section: Small Vessel Obstruction and Myocardial Ischemia In Fdmentioning

confidence: 99%

“…This observation, even if limited by the small size of the cohort, is consistent with previous studies showing no significant changes in myocardial blood flow, flow reserve, and coronary vascular resistance after an intermediate term of ERT. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Histopathologic studies with a longer-term follow-up after ERT are needed to elucidate the potential reversibility of glycosphingolipid deposition and lumen narrowing of intramural vessels.…”

Section: Response To Ertmentioning

confidence: 99%

Angina in Fabry Disease Reflects Coronary Small Vessel Disease

Chimenti

Morgante

Tanzilli

et al. 2008

Circ: Heart Failure

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Background-Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance are unclear. Methods and Results-Basal troponin I level, exercise stress test, single-photon emission computed tomography imaging with 99m Tc sestamibi, coronary angiography with thrombolysis in myocardial infarction (TIMI) frame count and left ventricular angiography and endomyocardial biopsy were obtained in 13 patients with FD with angina. Ratio of external to lumen diameter of intramural arteries (E/L ratio), myocyte diameter, and extent of fibrosis were morphometrically evaluated by using tissue sections. Controls for coronary angiography and histology were 25 patients with FD without angina and 20 mitral stenosis patients with normal left ventricular function. Troponin I level was elevated in 6 of the 13 patients. Exercise stress test showed evidence of myocardial ischemia, and single-photon emission computed tomography was positive for stress-induced perfusion defects in all patients with FD with angina. Epicardial coronaries were structurally normal but showed slow flow in all and were associated with aneurisms of posterior left ventricular wall in 3 cases. Histology showed remarkable lumen narrowing of most intramural arteries (mean E/L ratioϭ3.5Ϯ1.2; PϽ0.001 versus both control groups), because of hypertrophy and proliferation of smooth muscle and endothelial cells, both engulfed by glycosphingolipids. Replacement fibrosis exceeded that of both controls (PϽ0.001). Small vessel disease correlated with coronary slow flow and extent of fibrosis, but did not with patients' age, sex, and degree of left ventricular hypertrophy.

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“…Indeed, considerably higher glycosphingolipid levels have been demonstrated in serum and atherosclerotic lesions in atherogenic animal models and humans, whereas gangliosides have been reported to increase platelet adhesion to collagen and thrombus formation [6]. Accordingly, platelet function is known to be enhanced in FD [7], increasing the risk of thromboembolic events.…”

Section: Discussionmentioning

confidence: 97%

Coronary artery bypass grafting for Fabry's disease: veins more suitable than arteries?

et al. 2007

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The Possible Contribution of a General Glycosphingolipid Transporter, GM2 Activator Protein, to Atherosclerosis

Cited by 12 publications

References 37 publications

ID2 (Inhibitor of DNA Binding 2) Is a Rhythmically Expressed Transcriptional Repressor Required for Circadian Clock Output in Mouse Liver

ID2 (Inhibitor of DNA Binding 2) Is a Rhythmically Expressed Transcriptional Repressor Required for Circadian Clock Output in Mouse Liver

Angina in Fabry Disease Reflects Coronary Small Vessel Disease

Coronary artery bypass grafting for Fabry's disease: veins more suitable than arteries?

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