| 1. |
- Gertow, Joanna, et al.
(författare)
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Altered Protein Composition of Subcutaneous Adipose Tissue in Chronic Kidney Disease
- 2017
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Ingår i: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 2:6, s. 1208-1218
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Loss of renal function is associated with high mortality from cardiovascular disease (CVD). Patients with chronic kidney disease (CKD) have altered circulating adipokine and nonesterified fatty acid concentrations and insulin resistance, which are features of disturbed adipose tissue metabolism. Because dysfunctional adipose tissue contributes to the development of CVD, we hypothesize that adipose tissue dysfunctionality in patients with CKD could explain, at least in part, their high rates of CVD. Therefore we characterized adipose tissue from patients with CKD, in comparison to healthy controls, to search for signs of dysfunctionality. Methods: Biopsy samples of subcutaneous adipose tissue from 16 CKD patients and 11 healthy controls were analyzed for inflammation, fibrosis, and adipocyte size. Protein composition was assessed using 2dimensional gel proteomics combined with multivariate analysis. Results: Adipose tissue of CKD patients contained significantly more CD68-positive cells, but collagen content did not differ. Adipocyte size was significantly smaller in CKD patients. Proteomic analysis of adipose tissue revealed significant differences in the expression of certain proteins between the groups. Proteins whose expression differed the most were a-1-microglobulin/ bikunin precursor (AMBP, higher in CKD) and vimentin (lower in CKD). Vimentin is a lipid droplet-associated protein, and changes in its expression may impair fatty acid storage/mobilization in adipose tissue, whereas high levels of AMBP may reflect oxidative stress. Discussion: These findings demonstrate that adipose tissue of CKD patients shows signs of inflammation and disturbed functionality, thus potentially contributing to the unfavorable metabolic profile and increased risk of CVD in these patients.
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| 2. |
- Gertow, Joanna
(författare)
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Characterisation of human adipose tissue : ceramide metabolism, depot differences and evaluation of dysfunctionality
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Normal adipose tissue function is necessary for maintaining proper energy balance, as both excess and absence of this tissue lead to metabolic disturbances, such as insulin resistance. Adipose tissue can be dysfunctional in many ways, including disturbances in adipocyte size, lipolysis rate, adipokine secretion, inflammation, fibrosis or oxidative stress. Recently ceramides have been proposed as candidate molecules that mediate the development of adipocyte insulin resistance. The aim of this thesis is to evaluate different aspects of dysfunctionality in human adipose depots in relation to their potential contribution to insulin resistance and cardiovascular disease. Paper I and II focus on the role of ceramides in human adipose tissue. We show that in obese women with high liver fat increased ceramide content in the subcutaneous adipose depot is most probably due to the increased sphingomyelin hydrolysis rather than de novo production. Moreover, sphingomyelinases, that are responsible for this reaction, are present in areas rich in apolipoprotein B, which may suggest that circulating lipoproteins may be a source of sphingomyelin for the local ceramide production within adipose tissue. Additionally, we show increased ceramide levels in the mediastinal as compared to the subcutaneous adipose tissue and show that ceramides in this depot are associated with inflammatory processes. In our unpublished data we demonstrate that ceramide induces inflammatory cytokine expression in both macrophages and adipocytes. Paper III investigates whether the mediastinal depot shows characteristics of brown adipose tissue. A comparison of several markers of brown and white fat between subcutaneous and mediastinal adipose tissue reveals that the mediastinal fat has higher expression levels of some brown (UCP1, PPARGC1A) and lower expression levels of white (SHOX9, HOXC8) markers. Gene ontology analysis indicates that mediastinal depot is enriched in genes related to mitochondrial function. In some sections of mediastinal fat positive UCP1 staining and presence of multilocular cells are observed. In Paper IV we investigate whether adipose tissue in patients with chronic kidney disease is dysfunctional. We report that subcutaneous adipose tissue in patients with kidney failure is characterized by higher numbers of phagocytic cells and smaller adipocytes, but shows no signs of fibrosis as compared to healthy subjects. Additionally, proteomic analysis shows differential expression patterns between the patients and controls. Among the proteins expressed at higher levels in the patients, alpha-1-microglobulin/bikunin precursor is the most significant and among those expressed at lower levels in the patients, the most significant is vimentin – a protein known to be involved in lipid droplet metabolism. In summary, the work presented in this thesis demonstrates that adipose tissue ceramides can promote local inflammation, a process strongly linked to insulin resistance. Moreover, the mediastinal adipose depot shows some signs of brown fat, however the functional consequences remain to be evaluated. Finally, uremic adipose tissue shows adverse protein composition, which together with an increased number of phagocytic cells and smaller adipocyte size indicates that uremic adipose tissue is dysfunctional, which could lead to increased cardiovascular risk in chronic kidney disease patients.
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| 3. |
- Kolak, Maria, et al.
(författare)
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Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue
- 2012
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Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue.METHODS: Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject.RESULTS: Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot.CONCLUSIONS: Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.
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