Glycosphingolipid synthesis and proliferation in a renal cell line grown in high glucose

El-Khatib, Mustafa; Radin, Norman S.; Shayman, James A.

doi:10.1152/ajprenal.1996.270.3.f476

Cited by 11 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase in glucosylceramide mass does not appear to reflect a change in glucosylceramide synthase mass or localization, as demonstrated by immunohistochemistry. Even though we have not ruled out a change in enzymatic activity of glucosylceramide synthase, our data support studies from the Shayman Laboratory (37), where an increase in renal glucosylceramide mass at the expense of ceramide was associated with an increase in UDP-glucose and not glucosylceramide synthase activity (37,62). Alternatively, the inability of short-term fasting or insulin treatment to diminish glucosylceramide mass may reflect an inability of glucosylceramidase to reduce these levels within this time period.…”

Section: Discussionsupporting

confidence: 64%

Diabetes Alters Sphingolipid Metabolism in the Retina

et al. 2006

View full text Add to dashboard Cite

Dysregulated sphingolipid metabolism causes neuronal cell death and is associated with insulin resistance and diseases. Thus, we hypothesized that diabetes-induced changes in retinal sphingolipid metabolism may contribute to neuronal pathologies in diabetic retinopathy. ESI-MS/MS was used to measure ceramide content and ceramide metabolites in whole retinas after 2, 4, and 8 weeks of streptozotocin-induced diabetes. After 4 and 8 weeks of diabetes, a ϳ30% decrease in total ceramide content was observed, concomitant with a significant ϳ30% increase in glucosylceramide levels in fed diabetic rats compared with their age-matched controls. Acute insulin therapy as well as a short-term lowering of glucose via fasting did not affect the increase in glucosylceramide composition. To assess the putative biological consequences of the increase in glucosylceramide composition, R28 retinal neurons were treated with glucosylceramide synthase inhibitors. Inhibiting glycosphingolipid metabolism increased insulin sensitivity in retinal neurons. Glycosphingolipid inhibitors augmented insulin-stimulated p70 S6kinase activity in the presence of inhibitory concentrations of high glucose or glucosamine. Inhibition of glycosphingolipid synthesis also suppressed glucosamine-and interleukin-1␤-induced death. Consistent with these inhibitor studies, pharmacological accumulation of glycosphingolipids increased activation of the endoplasmic reticulum stress response, a putative modulator of insulin resistance and neuronal apoptosis. It is speculated that an increase in glucosylceramide, and possibly higher-order glycosphingolipids, could contribute to the pathogenesis of diabetic retinopathy by contributing to local insulin resistance, resulting in neuronal cell death. Thus, dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes, and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy. Diabetes 55: [3573][3574][3575][3576][3577][3578][3579][3580] 2006

show abstract

Section: Discussionsupporting

confidence: 64%

Diabetes Alters Sphingolipid Metabolism in the Retina

et al. 2006

View full text Add to dashboard Cite

show abstract

“…In support of this mechanism, evidence has shown that increased glucose uptake also leads to increased flux into glycogen synthesis [Kroemer and Pouyssegur, ], which is elevated both at baseline and in response to external stress in the neoplastic cell [Cori and Cori, ; Tsavachidou et al, ; Iida et al, ]. Furthermore, increased glucose availability has been previously shown to increase intracellular UDP‐glucose levels in the kidney in rat models of diabetes [Needleman et al, ; Spiro, ], an increase which was later shown to elevate GSL levels [Zador et al, ; el‐Khatib et al, ]. In that study, it was hypothesized that UDP‐glucose is utilized by GCS to form GlcCer through its addition to ceramide in diabetic conditions within the kidney.…”

Section: Discussionmentioning

confidence: 96%

“…Indeed, work in diabetic models does indicate a correlation between glucose uptake and GSL production. In a mouse model of type 1 diabetes mellitus (DM1), both UDP‐glucose [Needleman et al, ] and glycosphingolipid levels are elevated in the kidney in response to increased plasma concentrations of glucose [Zador et al, ; el‐Khatib et al, ]. Conversely, inhibition of GSL production via GCS improves glucose tolerance in animal models of DM1 [Zhao et al, ].…”

mentioning

confidence: 99%

Glucose Availability and Glycolytic Metabolism Dictate Glycosphingolipid Levels

Stathem

Marimuthu

O’Neal

et al. 2014

J of Cellular Biochemistry

View full text Add to dashboard Cite

Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, those of bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its implications in cancer have been at the forefront of cancer research for over 90 years. More recently, the role of sphingolipids in cancer cell metabolism has gained recognition, notably ceramide's essential role in programmed cell death and the role of the glucosylceramide synthase (GCS) in chemotherapeutic resistance. Despite this knowledge, a direct link between these two fields has yet to be definitively drawn. Herein, we show that in a model of highly glycolytic cells, generation of the glycosphingolipid (GSL) glucosylceramide (GlcCer) by GCS was elevated in response to increased glucose availability, while glucose deprivation diminished GSL levels. This effect was likely substrate dependent, independent of both GCS levels and activity. Conversely, leukemia cells with elevated GSLs showed a significant change in GCS activity, but no change in glucose uptake or GCS expression. In a leukemia cell line with elevated GlcCer, treatment with inhibitors of glycolysis or the pentose phosphate pathway (PPP) significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of pro-apoptotic sphingolipid ceramide increased. Taken together, we have shown that there exists a definitive link between glucose metabolism and GSL production, laying the groundwork for connecting two distinct yet essential metabolic fields in cancer research. Furthermore, we have proposed a novel combination therapeutic option targeting two metabolic vulnerabilities for the treatment of leukemia.

show abstract

“…Exposure to high levels of glucose increased the proliferation of smooth muscle cells [32] Cont. 25mM 50mM PBS Cont.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the Proangiogenic Functions of Adipose Tissue–Derived Stromal Cells Isolated from Diabetic Rats

Kim

et al. 2008

Stem Cells and Development

View full text Add to dashboard Cite

Cardiovascular complications in diabetic patients have been reported to be related to the impaired proangiogenic actions of endothelial progenitor cells. In this study, we investigated the functions of adipose tissuederived stromal cells (ASCs) in diabetes. We induced type I diabetes in rats by a intraperitoneal injection of 60 mg/kg of streptozotocin (STZ) and type II diabetes by the combined treatment of high fat diet and 45 mg/kg of STZ. Rat ASCs (rASCs) isolated from the adipose tissues in the interscapular and abdominal region of type I or type II diabetic rats showed lower proliferating ability than those of control rats. Diabetic rASCs showed lower blood ow recovery than those of control rats in a hindlimb ischemia model of nude mouse. When ASCs isolated from rat and human were exposed to high glucose concentrations, their proliferating abilities and improved blood ow in a hindlimb ischemia model were compromised, compared with ASCs that were maintained at control glucose concentrations. However, the same concentrations of mannitol did not affect these characteristics. Exposure of human ASCs (hASCs) to high glucose concentrations increased reactive oxygen species (ROS) production, and the addition of ROS scavengers [N-acetylcysteine (NAC) or catalase] to high glucose media partially decreased the high glucose-induced inhibitory effect on proliferating ability in hASCs. However, hASCs treated with high glucose medium for 6 days showed lower proliferation in control culture medium, which was not recovered by the addition of NAC or catalase. These data indicate that ASCs isolated from diabetic rats and exposed at high concentration of glucose have an impaired proangiogenic action and that the functional impairment is partly due to ROS generated by chronic exposure to high glucose concentrations.

show abstract

Glycosphingolipid synthesis and proliferation in a renal cell line grown in high glucose

Cited by 11 publications

References 0 publications

Diabetes Alters Sphingolipid Metabolism in the Retina

Diabetes Alters Sphingolipid Metabolism in the Retina

Glucose Availability and Glycolytic Metabolism Dictate Glycosphingolipid Levels

Alterations in the Proangiogenic Functions of Adipose Tissue–Derived Stromal Cells Isolated from Diabetic Rats

Contact Info

Product

Resources

About