Plasma glycosphingolipids in diabetics and normals

Kremer, Gidon; Atzpodien, W.; Schnellbächer, Elisabeth

doi:10.1007/bf01469685

Cited by 20 publications

(16 citation statements)

References 5 publications

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“…In humans, there is an inverse correlation between metabolic disease and serum ceramides 90, 91 . In rodent models, ceramide accumulation is correlated with toxicity that leads to metabolic diseases, in particular the promotion of insulin resistance 92 .…”

Section: Role Of Intestinal Fxr In the Regulation Ceramidesmentioning

confidence: 99%

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

2016

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The gut microbiota is associated with metabolic diseases including obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD), as demonstrated by correlative studies and by transplant of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse metabolic phenotypes. This was due to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-β-muricholic acid (T-β-MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD-induced obesity, insulin resistance and NAFLD thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist glycine-β-muricholic acid (Gly-MCA) that is resistant to BSH, was developed that when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decreased in adverse metabolic phenotype by tempol, antibiotics and Gly-MCA was due to decreased serum ceramides. Mice lacking FXR in intestine also have lower serum ceramides, are metabolic fit and resistant to HFD-induced metabolic disease, and this is reversed by injection of C16:0 ceramide. In mouse ileum, due to the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered, they are repressed, which likely accounts for the decrease in serum ceramides. These studies reveal that ceramides produced in the ileum under control of FXR, influence metabolic diseases.

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Section: Role Of Intestinal Fxr In the Regulation Ceramidesmentioning

confidence: 99%

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

2016

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“…Increased levels of sphingolipids such as glycosphingolipids (70), ceramide (71, 72), sphingosine (73), and sphinganine (72, 73) have been described in the plasma of patients with diabetes. More recently, it has become clear that the intracellular sphingolipid composition in podocytes and other cells of the kidney glomerulus may contribute to the pathogenesis and progression of the disease (Table 1).…”

Section: Sphingolipid Accumulation In Glomerular Disease Of Non-genetmentioning

confidence: 99%

Podocyte Pathology and Nephropathy â€“ Sphingolipids in Glomerular Diseases

Merscher

Fornoni

2014

Front. Endocrinol.

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Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay–Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann–Pick, and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarly, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD), HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS), and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is expressed in podocytes where it modulates acid sphingomyelinase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed.

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“…It has long been appreciated that sphingolipid levels are perturbed in the blood plasma of diabetic patients. The first such finding indicated that glycosphingolipids were elevated in the plasma of some groups of diabetic human patients (Kremer et al 1975). This was later confirmed by a study demonstrating that glucosylceramide was elevated in the plasma of diabetics (Serlie et al 2007).…”

Section: Sphingolipids As Biomarkers Of Diabetesmentioning

confidence: 99%

Sphingolipids in Obesity, Type 2 Diabetes, and Metabolic Disease

Russo

Ross

Cowart

2013

Handbook of Experimental Pharmacology

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Metabolic disease, including obesity and type 2 diabetes, constitutes a major emerging health crisis in Western nations. Although the symptoms and clinical pathology and physiology of these conditions are well understood, the molecular mechanisms underlying the disease process have largely remained obscure. Sphingolipids, a lipid class with both signaling and structural properties, have recently emerged as key players in most major tissues affected by diabetes and are required components in the molecular etiology of this disease. Indeed, sphingolipids have been shown to mediate loss of insulin sensitivity, to promote the characteristic diabetic pro-inflammatory state, and to induce cell death and dysfunction in important organs such as the pancreas and heart. Furthermore, plasma sphingolipid levels are emerging as potential biomarkers for the decompensation of insulin resistance to frank type 2 diabetes. Despite these discoveries, the roles of specific sphingolipid species and sphingolipid metabolic pathways remain obscure, and newly developed experimental approaches must be employed to elucidate the detailed molecular mechanisms necessary for rational drug development and other clinical applications.

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Plasma glycosphingolipids in diabetics and normals

Cited by 20 publications

References 5 publications

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

Podocyte Pathology and Nephropathy â€“ Sphingolipids in Glomerular Diseases

Sphingolipids in Obesity, Type 2 Diabetes, and Metabolic Disease

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