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- Elhadad, M. A., et al.
(author)
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Deciphering the plasma proteome of type 2 diabetes
- 2020
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2766-2778
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Journal article (peer-reviewed)abstract
- With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1,000 plasma proteins in the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 993, 110 cases), with subsequent replication in the third wave of the Nord-Trøndelag Health Study (HUNT3) cohort (n = 940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status, and hypertension. Addition-ally, we investigated associations with incident type 2 diabetes and performed two-sample bidirectional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which 8 are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor–binding protein 2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone–binding globulin on type 2 diabetes. In conclusion, our high-throughput pro-teomics study replicated previously reported type 2 diabetes–protein associations and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes. © 2020 by the American Diabetes Association.
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| 2. |
- Egana, I, et al.
(author)
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Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
- 2017
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15453-
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Journal article (peer-reviewed)abstract
- Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
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| 5. |
- Saarikangas, J, et al.
(author)
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Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia
- 2011
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In: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 124:8Pt 8, s. 1245-1255
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Journal article (peer-reviewed)abstract
- MIM/MTSS1 is a tissue-specific regulator of plasma membrane dynamics, whose altered expression levels have been linked to cancer metastasis. MIM deforms phosphoinositide-rich membranes through its I-BAR domain and interacts with actin monomers through its WH2 domain. Recent work proposed that MIM also potentiates Sonic hedgehog (Shh)-induced gene expression. Here, we generated MIM mutant mice and found that full-length MIM protein is dispensable for embryonic development. However, MIM-deficient mice displayed a severe urinary concentration defect caused by compromised integrity of kidney epithelia intercellular junctions, which led to bone abnormalities and end-stage renal failure. In cultured kidney epithelial (MDCK) cells, MIM displayed dynamic localization to adherens junctions, where it promoted Arp2/3-mediated actin filament assembly. This activity was dependent on the ability of MIM to interact with both membranes and actin monomers. Furthermore, results from the mouse model and cell culture experiments suggest that full-length MIM is not crucial for Shh signaling, at least during embryogenesis. Collectively, these data demonstrate that MIM modulates interplay between the actin cytoskeleton and plasma membrane to promote the maintenance of intercellular contacts in kidney epithelia.
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| 6. |
- Vehmas, A. P., et al.
(author)
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Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse
- 2016
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In: Journal of Proteomics. - : Elsevier BV. - 1874-3919. ; 133, s. 66-75
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Journal article (peer-reviewed)abstract
- Estrogens are suggested to lower the risk of developing metabolic syndrome in both sexes. In this study, we investigated how the increased circulating estrogen-to-androgen ratio (E/A) alters liver lipid metabolism in males. The cytochrome P450 aromatase (P450arom) is an enzyme converting androgens to estrogens. Male mice overexpressing human aromatase enzyme (AROM + mice), and thus have high circulating E/A, were used as a model in this study. Proteomics and gene expression analyses indicated an increase in the peroxisomal beta-oxidation in the liver of AROM + mice as compared with their wild type littermates. Correspondingly, metabolomic analysis revealed a decrease in the amount of phosphatidylcholines with long-chain fatty acids in the plasma. With interest we noted that the expression of Cyp4a12a enzyme, which specifically metabolizes arachidonic acid (AA) to 20-hydroxy AA, was dramatically decreased in the AROM + liver. As a consequence, increased amounts of phospholipids having AA as a fatty acid tail were detected in the plasma of the AROM + mice. Overall, these observations demonstrate that high circulating E/A in males is linked to indicators of higher peroxisomal beta-oxidation and lower AA metabolism in the liver. Furthermore, the plasma phospholipid profile reflects the changes in the liver lipid metabolism. (C) 2015 Elsevier B.V. All rights reserved.
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