| 1. |
|
|
| 2. |
- Uhlén, Mathias, et al.
(author)
-
The human secretome
- 2019
-
In: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 12:609
-
Journal article (peer-reviewed)abstract
- The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.
|
|
| 3. |
- Abdellah, Tebani, et al.
(author)
-
Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Journal article (peer-reviewed)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
|
|
| 4. |
- Franck, Niclas, et al.
(author)
-
Identification of adipocyte genes regulated by caloric intake
- 2011
-
In: Journal of Clinical Endocrinology and Metabolism. - : Endocrine society. - 0021-972X .- 1945-7197. ; 96:2, s. E413-E418
-
Journal article (peer-reviewed)abstract
- CONTEXT: Changes in energy intake have marked and rapid effects on metabolic functions and some of the effects may be due to changes in adipose tissue gene expression that precede alterations in body weight. OBJECTIVE: To identify genes in adipose tissue regulated by changes in caloric intake independent of changes in body weight. RESEARCH DESIGN AND METHODS: Obese subjects were given a very-low calorie diet (VLCD; 450 kcal/day) for 16 weeks. After the diet, ordinary food was gradually reintroduced during 2 weeks while there were minimal changes in body weight. Adipose tissue gene expression was measured by microarray analysis. First, genes regulated during caloric restriction and in the opposite direction during the weight stable re-feeding phase were identified. To verify opposite regulation to that observed during caloric restriction, identified genes were further analyzed using adipocyte expression profiles from healthy subjects before and after overfeeding. Results were confirmed using real time PCR or immunoassay. RESULTS: Using a significance level of p<0.05 for all comparisons, 52 genes were downregulated and 50 were up-regulated by caloric restriction and regulated in the opposite direction by re-feeding and overfeeding. Among these were genes that affect lipogenesis (ACLY, ACACA, FASN, SCD), protein synthesis (4EBP1, 4EBP2), beta-oxidation (CPT1B), liberation of fatty acids (CIDEA) and glyceroneogenesis (PCK2). Interestingly, several of these are under control of the master regulator mTOR. CONCLUSIONS: The observed transcriptional changes indicate that mTOR plays a central role in the control of diet-regulated adipocyte genes involved in lipogenesis and protein synthesis.
|
|
| 5. |
- Gummesson, Anders, 1973, et al.
(author)
-
Relations of Adipose Tissue Cell Death-Inducing DFFA-like Effector A Gene Expression to Basal Metabolic Rate, Energy Restriction and Obesity: Population-based and Dietary Intervention Studies.
- 2007
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:12, s. 4759-65
-
Journal article (peer-reviewed)abstract
- Context: Cell death-inducing DFFA-like effector A (CIDEA) could be a potential target for the treatment of obesity via the modulation of metabolic rate, based on the findings that CIDEA inhibits the brown adipose tissue uncoupling process in rodents. Objective: To investigate the putative link between CIDEA and basal metabolic rate in humans, and to further elucidate the role of CIDEA in human obesity. Design: We have explored CIDEA gene expression in adipose tissue in two different human studies: A cross-sectional and population-based study assessing body composition and metabolic rate (Mölndal Metabolic study, n=92), and a longitudinal intervention-study of obese subjects treated with a very low calorie diet (VLCD study, n=24). Results: The CIDEA gene was predominantly expressed in adipocytes as compared to other human tissues. CIDEA gene expression in adipose tissue was inversely associated with basal metabolic rate independently of body composition, age and gender (p=0.014). VLCD induced an increase in adipose tissue CIDEA expression (p<0.0001) with a subsequent decrease in response to refeeding (p<0.0001). Reduced CIDEA gene expression was associated with a high body fat content (p<0.0001) and with high insulin levels (p<0.01). No dysregulation of CIDEA expression was observed in individuals with the metabolic syndrome when compared with BMI-matched controls. In a separate sample of VLCD-treated subjects (n=10), uncoupling protein 1 expression was reduced during diet (p=0.0026) and inversely associated with CIDEA expression (p=0.0014). Conclusion: The findings are consistent with the concept that CIDEA plays a role in adipose tissue energy expenditure.
|
|
| 6. |
- Magnusson, Björn, 1976, et al.
(author)
-
Cell death-inducing DFF45-like effector C is reduced by caloric restriction and regulates adipocyte lipid metabolism.
- 2008
-
In: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 57:9, s. 1307-13
-
Journal article (peer-reviewed)abstract
- Members of the cell death-inducing DFF45-like effector (CIDE) gene family have been shown to regulate lipid metabolism. In this article, we report that the third member of the human CIDE family, CIDEC, is down-regulated in response to a reduced caloric intake. The down-regulation was demonstrated by microarray and real-time polymerase chain reaction analysis of subcutaneous adipose tissue in 2 independent studies on obese patients undergoing treatment with a very low calorie diet. By analysis of CIDEC expression in 65 human tissues, we conclude that human CIDEC is predominantly expressed in subcutaneous adipocytes. Together, these observations led us to investigate the effect of decreased CIDEC expression in cultured 3T3-L1 adipocytes. Small interfering RNA-mediated knockdown of CIDEC resulted in an increased basal release of nonesterified fatty acids, decreased responsiveness to adrenergic stimulation of lipolysis, and increased oxidation of endogenous fatty acids. Thus, we suggest that CIDEC is a regulator of adipocyte lipid metabolism and may be important for the adipocyte to adapt to changes in energy availability.
|
|
| 7. |
- Behre, Carl Johan, 1968, et al.
(author)
-
Dissociation between adipose tissue expression and serum levels of adiponectin during and after diet-induced weight loss in obese subjects with and without the metabolic syndrome
- 2007
-
In: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 56:8, s. 1022-8
-
Journal article (peer-reviewed)abstract
- The study aimed to examine if dysmetabolic subjects (MetS+) have lower adiponectin gene expression and lower circulating adiponectin levels than non-dysmetabolic obese subjects (MetS-) at baseline, if adiponectin expression and adiponectin concentration rise more in the dysmetabolic group during weight loss, and if v-SNARE Vti1a (vesicle transport soluble NSF attachment protein receptor vps10p tail interacting 1a) expression increases during the weight loss, as a mechanism for increased adiponectin secretion. Twenty-one obese MetS+ and 19 obese MetS- subjects underwent a very low-energy diet for 16 weeks followed by 2 weeks of refeeding. Abdominal subcutaneous adipose tissue biopsies and blood samples were taken before, during, and after dieting for DNA microarray, reverse transcriptase-polymerase chain reaction, and biochemical analyses. Serum adiponectin was also assessed in a sex- and age-matched healthy, nonobese reference group. Weight decreased by 26.3+/-9.8 kg in the MetS+ group and 28.2+/-8.4 kg in the MetS- group with concomitant reductions in insulin, hemoglobin A1c, and triglycerides that were more pronounced in the MetS+ group. Initially, the MetS+ subjects had lower serum adiponectin, but the differences disappeared at week 8, with a continuous increase in serum adiponectin throughout the study in both groups to a level that was higher than in the reference group. The expression of adiponectin and v-SNARE Vti1a did not differ between the groups or over time. In conclusion, obese subjects with the metabolic syndrome had lower circulating adiponectin than subjects without the syndrome. Weight loss increased serum levels of adiponectin without a parallel increase in adiponectin gene expression. The mechanisms involved in the regulation of adiponectin levels merits further investigation.
|
|
| 8. |
- Behre, Carl Johan, 1968, et al.
(author)
-
Hypoxia-inducible factor 1 is correlated to serum adiponectin levels and measures of obesity and insulin sensitivity in vivo
- 2009
-
In: International Congress on Prediabetes and the Metabolic Syndrome.
-
Conference paper (other academic/artistic)abstract
- Title: Hypoxia-inducible factor 1 is correlated to serum adiponectin levels and measures of obesity and insulin sensitivity in vivo Background: Hypoxia has been shown to decrease adiponectin in vitro. Adiponectin levels are negatively associated to type 2 diabetes and cardiovascular diseases. Recently, it was shown that Hypoxia-inducible factor 1α (HIF-1) regulates adiponectin expression in murine cardiomyocytes. The present study was performed to examine the association between HIF-1 expression and serum adiponectin levels, measures of adiposity and insulin resistance in humans. Methods: Abdominal subcutaneous adipose tissue biopsies were obtained from 24 subjects diagnosed with and without the metabolic syndrome. HIF-1 gene expression was assessed by individual DNA microarray analyses. Adipose tissue depots were assessed with computerized tomography. Anthropometrics were performed. Circulating levels of insulin, adiponectin, leptin, cholesterol, high-sensitivity C - reactive protein (hs-CRP) and fasting levels of insulin and glucose were measured by standard laboratory procedures. Results: In a univariate analysis, HIF-1 expression levels correlate to BMI (r=0.42, p=0.04), WHR (r=0.55, p=0.0058), total adipose tissue (r=0.46, p=0.022), subcutaneous adipose tissue ( r=0.49, p= 0.016),liver fat (r=0.44, p=0.030), fasting insulin (r=0.46, p=0.023), HOMA-index (r=0.46, p=0.023) and serum adiponectin (r= -0.42, p=0.0418). We observed no statistically significant correlations between HIF-1 gene expression and visceral adipose tissue, systolic blood pressure, serum cholesterol, hs-CRP or serum leptin. HIF-1 gene expression did not differ between the groups. Conclusions: We report that expression of HIF-1 is correlated to serum adiponectin, insulin sensitivity and measures of adiposity. There were no statistical differences in expression of HIF-1 between subjects with or without the metabolic syndrome. In this cross-sectional analysis, no conclusions can be drawn about causality.
|
|
| 9. |
- Dobritzsch, Doreen, 1972-, et al.
(author)
-
beta-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity
- 2022
-
In: Molecular Genetics and Metabolism. - : Elsevier. - 1096-7192 .- 1096-7206. ; 136:3, s. 177-185
-
Journal article (peer-reviewed)abstract
- beta-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid to beta-alanine and beta-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete beta-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified beta-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine. Analysis of UPB1, encoding beta-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant beta-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased beta-ureidopropionase activity. Analysis of the crystal structure of human beta-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional beta-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish beta-ureidopropionase patients, indicating that beta-ureidopropionase deficiency may be more common than anticipated.
|
|
| 10. |
- Dodig-Crnkovic, Tea, et al.
(author)
-
Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling
- 2020
-
In: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 57
-
Journal article (peer-reviewed)abstract
- Background: Precision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate. Methods: To provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals' short-term health trajectories. Findings: We found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed that 49% of the protein profiles were stable over one year. We also identified eight networks of proteins in which 11-242 proteins covaried over time. For each participant, there were unique protein profiles of which some could be explained by associations to genetic variants. Interpretation: This observational and non-interventional study identifyed noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. To enable more personal hence precise assessments of health states, longitudinal profiling of circulating proteomes can provide a valuable component for precision medicine approaches.
|
|
