Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus

Ferderbar, Simone; Pereira, Edimar Cristiano; Apolinário, Elaine; Bertolami, Marcelo Chiara; Faludi, André Árpád; Monte, Osmar; Calliari, Luís Eduardo; Sales, José Emanuel de Souza; Gagliardi, Antônio; Xavier, Hermes Tóros; Abdalla, Dulcinéia Saes Parra

doi:10.1002/dmrr.645

Cited by 72 publications

(62 citation statements)

References 37 publications

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“…In obese type 2 diabetic patients, plasma 9-and 13-HODE levels are decreased by troglitazone therapy (46), but no information is available regarding plasma or lipoprotein-related HODE concentrations in T1DM. However, Ferderbar et al (47) recently reported significant increases in total cholesterol oxides and 7-hydroxycholesterol in plasma of children and young adults with T1DM, even in the absence of hypercholesterolemia. Martin-Gallan et al (48) have also reported increased levels of LPOs and the lipid peroxidation product, malondialdehyde, in plasma of T1DM patients, independent of complication status.…”

Section: Discussionmentioning

confidence: 97%

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Brock

Jenkins

Lyons

et al. 2008

Journal of Lipid Research

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Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q 84 -M 86 -K 88 , W 108 -M 112 -R 116 , and L 144 -M 148 -R 149 . These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met 86 , Met 112 , and Met 148 ) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N : -malondialdehyde-lysine or N : -(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.-Brock, J.

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Section: Discussionmentioning

confidence: 97%

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Brock

Jenkins

Lyons

et al. 2008

Journal of Lipid Research

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“…In this study we found that both Lxrα and Lxrβ mRNA was present and significantly upregulated by the addition of LXR agonists to beta cells, suggesting that LXR elevation might be involved in pancreatic beta cell dysfunction in type 2 diabetes. Moreover, levels of oxysterols, endogenous activators of LXRs, are markedly upregulated in the blood plasma of patients with type 2 diabetes [34,35]. Importantly, Mitro et al [36] demonstrated that glucose also activates LXRs at physiological concentrations.…”

Section: Discussionmentioning

confidence: 99%

Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest

et al. 2008

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Aims/hypothesis Liver X receptors (LXRs) are important transcriptional regulators of lipid homeostasis and proliferation in several cell types. However, the roles of LXRs in pancreatic beta cells have not been fully established. The aim of this study was to investigate the effects of LXRs on pancreatic beta cell proliferation. Methods Gene expression was analysed using real-time RT-PCR. Transient transfection and reporter gene assays were used to determine the transcriptional activity of LXRs in pancreatic beta cells. Cell viability and proliferation were analysed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), DNA fluorometric, BrdU labelling and [3 H]thymidine incorporation assays. Cell cycle distribution was investigated by flow cytometry analysis. Adenovirus-based RNA interference was used to knockdown LXRα, LXRβ and p27 in MIN6 cells and mouse islets.Results We found that both Lxrα (also known as Nr1h3) and Lxrβ (also known as Nr1h2) were expressed and transactivated the LXR response element in HIT-T15 and MIN6 cells. Activation of LXRs dose-dependently inhibited pancreatic beta cell viability and proliferation. This was accompanied by beta cell cycle arrest at the G1 phase. Furthermore, LXR activation increased levels of the p27 protein by inhibiting its degradation. Knockdown of p27 reversed these effects of LXR activation on growth inhibition and cell cycle arrest. Conclusions/interpretation Our observations indicate that LXR activation inhibits pancreatic beta cell proliferation through cell cycle arrest. A well-known regulator of pancreatic beta cell cycle progression, p27, is upregulated and mediates the effects of LXRs on growth inhibition in beta cells. These observations suggest the involvement of aberrant activation of LXR in beta cell mass inadequacy, which is an important step in the development of type 2 diabetes.Keywords Beta cell . Cell cycle . Islet . LXR . p27 . Proliferation Abbreviations CMV cytomegalovirus GFP green fluorescent protein LXR liver X receptor LXRE liver X receptor response element MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide RNAi RNA interference SKP2 S-phase kinase-associated protein 2 siRNA small interfering RNA

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“…The plasma of patients with DM has been studied, and the oxysterols 7␣-and 7␤-OH-Ch, and 5␣,6␣-and 5␤,6␤-epoxy-Ch were measured. These oxysterols increased in the DM plasma, and these oxysterols have been suggested to be useful as biomarkers for oxidative damage in patients with DM (28).…”

Section: Nonenzymatically Formed Oxysterols In Pathophysiologymentioning

confidence: 98%

Cholesterol, Reactive Oxygen Species, and the Formation of Biologically Active Mediators

Murphy

Johnson

2008

Journal of Biological Chemistry

163

116

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Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus

Abstract: ChOx are suitable biomarkers of oxidative stress and may be useful in clinical studies to follow drug effects on lipid oxidative modifications in diabetic patients.

Cited by 72 publications

References 37 publications

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest

Cholesterol, Reactive Oxygen Species, and the Formation of Biologically Active Mediators

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