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- Bentinger, Magnus, et al.
(författare)
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Influence of liver-X-receptor on tissue cholesterol, coenzyme Q and dolichol content
- 2012
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Ingår i: Molecular membrane biology. - : Informa UK Limited. - 0968-7688 .- 1464-5203. ; 29:7, s. 299-308
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Tidskriftsartikel (refereegranskat)abstract
- The organ content of the mevalonate pathway lipids was investigated in liver-X-receptor (LXR) alpha, beta and double knockout mice. An extensive or moderate increase of total cholesterol in the double KO mice was found in all organs elicited by the increase of the esterified form. In LXR alpha and double KO mice, coenzyme Q (CoQ) was decreased in liver and increased in spleen, thymus and lung, while dolichol was increased in all organs investigated. This effect was confirmed using LXR-agonist GW 3965. Analysis of CoQ distribution in organelles showed that the modifications are present in all cellular compartments and that the increase of the lipid in mitochondria was the result of a net increase of CoQ without changing the number of mitochondria. It appears that LXR influences not only cellular cholesterol homeostasis but also the metabolism of CoQ and dolichol, in an indirect manner.
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- Catrina, Sergiu-Bogdan
(författare)
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Regulators of angiogenesis in diabetes and tumors
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis is tightly regulated in order to provide adequate supply of nutrients and oxygen for normal cellular function. Tissue oxygenation represents a balance between the requirement for oxygen to maintain the cellular energy level and the potential risk of cellular oxidative damage. The master regulator of oxygen homeostasis is Hypoxia inducible factor-1 (HIF-1). Our basic hypothesis was therefore that HIF modulation might be relevant for diseases characterised by dysregulated angiogenesis, such as diabetes mellitus and tumors. Chronic complications of diabetes are a major health problem, and a better understanding of their pathogenic mechanisms could offer a more rational therapy. Both hyperglycemia and hypoxia play important roles in the pathogenesis of diabetes complications and we propose that the interplay between these two factors is essential in determining the devellopement of chronic complications of diabetes. We demonstrated that high concentrations of glucose interfere with hypoxia-dependent stabilization of HIF-1alpha against proteasomal degradation in both primary human dermal fibroblasts and microvascular endothelial cells. The destabilizing effect of glucose was partially independent of prolyl hydroxylases (PHD). Hyperglycemia also inhibited transactivation and function of HIF-1 as demonstrated by a HRE (hypoxia responsive elements) reporter gene assay. In agreement with our in vitro observations we detect lower expression of HIF-1 alpha in diabetic wounds then in venous ulcers that share the same hypoxic environment but not the chronic exposure to hyperglycemia. Based on these findings we further investigated the potential therapeutic effect of HIF-1 alpha up-regulation in diabetic woundsby using DMOG, a chemical inducer of HIF-1 alpha which showed virtually no toxic effect on primary dermal fibroblasts in vitro. Local treatment with DMOG normalized the healing rate of experimental wounds in db/db mice suggesting that HIF-1 alpha modulation is a promising therapeutical approach for diabetic wounds. Dysregulated angiogenesis is also a hallmark of tumor diseases. Kaposi s sarcoma (KS) is a highly vascularised tumor, which depends strictly on angiogenetic stimuli. We have therefore investigated the HIF pathway in KS and its relation to the insulin like growth factor (IGF) system, known as a major factor in pathophysiology of different tumors. We demonstrated that KS cells express both HIF-1alpha and HIF-2 alpha even in normoxia and that IGF-I induced their expression, showing for the first time that a growth factor is able to induce accumulation of both HIFalpha congeners. HIF accumulation was followed by functional activation as demonstrated by a HRE reporter gene assay and by induction of HIF target genes (ex. VEGF). IGF-I induced accumulation of both HIF-1 alpha and HIF-2 alpha at a posttranscriptional level as demonstrated by qRT-PCR and cycloheximide chasing experiment and we suggest that IGF-I increased the translation of the alpha subunits. The clinical relevance of our findings was confirmed by the identification of high levels of both HIF isofoms in tumor cells in biopsies from patients with AIDS-related KS. It was further demonstrated that IGF-I and IGF-II are potent growth factors for KS cells and have an additive effect with VEGF. IGF-I receptor (IGF-IR) was identified as the receptor mediating the IGFs effect and we described an autocrine loop in KS cells in which IGF-II is the endogenous ligand for IGF-IR. Finally, it was demonstrated that blocking the IGF-IR with picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor, induced apoptosis and decreased HIF accumulation and function in KS cells, suggesting a potential future therapeutic approach. In conclusion, HIF is an important factor both in chronic complications of diabetes and in vascular tumor KS. We have highlighted that glucose and IGF-I regulate HIF by other mechanisms than the classic hypoxic regulation. Finally it was demonstrated that modulation of HIF can be a successful approach for treatment of both diabetic wounds and KS.
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| 7. |
- Chang, Ya-Ting, et al.
(författare)
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Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension
- 2015
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:1, s. 20-31
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Tidskriftsartikel (refereegranskat)abstract
- Aims Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH. Methods and results In normoxia, Hspg2(Delta 3/Delta 3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in the proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(Delta 3/Delta 3) compared with wild type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(Delta 3/Delta 3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(Delta 3/Delta 3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(Delta 3/Delta 3) compared with wild type. Conclusions Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.
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- Dalin, Frida, 1984-, et al.
(författare)
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Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.
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| 9. |
- dos Santos, Klinsmann Carolo, et al.
(författare)
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The impact of macronutrient composition on metabolic regulation : An Islet-Centric view
- 2022
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 236:4
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR). Methods: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2, and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2, and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate-rich or fat-rich meal (600 kcal) in a cross-over design. Plasma insulin and glucagon levels were measured at −30, −5, and 0 min, and every 30 min until 240 min after meal ingestion. Results: The IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels. Conclusion: The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.
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| 10. |
- Elksnis, Andris, 1993-
(författare)
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Pharmaceutical Protection of Beta-Cells in Diabetes : Using Tyrosine Kinase Inhibition and NOX4 Inhibitors
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes mellitus is a complex and heterogenous disease, with loss of beta-cell function and mass being a characteristic of not only type 1 diabetes (T1D), but also type 2 diabetes (T2D). In T1D, inappropriate inflammatory signaling is thought to participate in the autoimmune suppression and destruction of beta-cells. In T2D progressive insulin resistance with resulting glucolipotoxicity, increased inflammation and oxidative stress, drives islet amyloid formation and subsequent beta-cell exhaustion and failure. Even under best managed care, disease progression and eventual complications are unavoidable. New interventions that aim to improve beta-cell survival are highly needed. This thesis investigates two such possible interventions: the tyrosine kinase inhibitor Imatinib, and selective NADPH-oxidase inhibition.Imatinib mesylate, used in treatment of chronic myeloid leukemia and other malignancies, was soon after its introduction reported to possess anti-diabetic properties in both T1D and T2D patients undergoing treatment. Imatinib has been shown to prevent and reverse diabetes in NOD mice and improve glucose tolerance in high fat diet treated rats. In paper I, we aimed to characterize the mechanisms by which imatinib protects beta-cells. We found that imatinib inhibits complex I and II of the respiratory chain, leading to improved beta-cell survival through AMPK activation, reduced amyloid formation and protection against TXNIP upregulation.Oxidative stress may play a pivotal role in the development of beta-cell dysfunction and failure in T2D. The NADPH-oxidases are a family of 7 enzymes (NOX1-5 and DUOX 1-2), that produce reactive oxygen species that are important in various physiological processes but may, if excessively activated, also be a source for oxidative stress in T2D. In paper II, we evaluate novel selective NOX inhibitors as protective agents against in vitro induced human beta-cell stress. Selective NOX4 inhibition protected beta-cells against both cytokines and high-glucose + palmitate. In paper III we found that NOX4 inhibition increased mitochondrial membrane potential, mitochondrial reactive oxygen species and ATP/ADP ratio in a human beta-cell line, and this was paralleled with protection against human islet cell death when challenged with high-glucose and palmitate. Finally, in paper IV, we attempt to apply these findings in vivo, by transplanting athymic diabetic mice with human islets and treating them with a NOX4 inhibitor over a period of 4 weeks. Treated mice achieved lower blood glucose levels and water consumption throughout the treatment period, and apoptotic rates of insulin-positive human cells, measured as co-localization of insulin and cleaved caspase-3, were greatly reduced.
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