| 1. |
- Hilvo, Mika, et al.
(författare)
-
Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients
- 2014
-
Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 134:7, s. 1725-1733
-
Tidskriftsartikel (refereegranskat)abstract
- Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
|
|
| 2. |
- Hilvo, Mika, et al.
(författare)
-
Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression
- 2011
-
Ingår i: Cancer Research. - Philadelphia, PA, USA : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 71:9, s. 3236-45
-
Tidskriftsartikel (refereegranskat)abstract
- Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.
|
|
| 3. |
- Kekkonen, Riina-A., et al.
(författare)
-
Effect of probiotic Lactobacillus rhamnosus GG intervention on global serum lipidomic profiles in healthy adults
- 2008
-
Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 14:20, s. 3188-3194
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the effect of three weeks' intervention with a probiotic Lactobacillus rhamnosus GG (LGG) bacteria on global serum lipidomic profiles and evaluate whether the changes in inflammatory variables (CRP, TNF-alpha and IL-6) are reflected in the global lipidomic profiles of healthy adults.METHODS: We performed UPLC/MS-based global lipidomic platform analysis of serum samples (n = 26) in a substudy of a randomised, double-blind, placebo-controlled 3-wk clinical intervention trial investigating the immunomodulatory effects of probiotics in healthy adults.RESULTS: A total of 407 lipids were identified, corresponding to 13 different lipid classes. Serum samples showed decreases in the levels of lysophosphatidylcholines (LysoGPCho), sphingomyelins (SM) and several glycerophosphatidylcholines (GPCho), while triacylglycerols (TAG) were mainly increased in the probiotic LGG group during the intervention. Among the inflammatory variables, IL-6 was moderately associated by changes in global lipidomic profiles, with the top-ranked lipid associated with IL-6 being the proinflammatory LysoGPCho (20:4). There was a weak association between the lipidomic profiles and the two other inflammatory markers, TNF-alpha and CRP.CONCLUSION: This was the first study to investigate the effects of probiotic intervention on global lipidomic profiles in humans. There are indications that probiotic LGG intervention may lead to changes in serum global lipid profiles, as reflected in decreased GPCho, LysoGPCho and SM as well as mainly increased TAG.
|
|
| 4. |
- Koivuniemi, Artturi, et al.
(författare)
-
Interfacial properties of high-density lipoprotein-like lipid droplets with different lipid and apolipoprotein A-I compositions
- 2013
-
Ingår i: Biophysical Journal. - : Elsevier. - 0006-3495 .- 1542-0086. ; 104:10, s. 2193-2201
-
Tidskriftsartikel (refereegranskat)abstract
- The surface properties of high-density lipoproteins (HDLs) are important because different enzymes bind and carry out their functions at the surface of HDL particles during metabolic processes. However, the surface properties of HDL and other lipoproteins are poorly known because they cannot be directly measured for nanoscale particles with contemporary experimental methods. In this work, we carried out coarse-grained molecular dynamics simulations to study the concentration of core lipids in the surface monolayer and the interfacial tension of droplets resembling HDL particles. We simulated lipid droplets composed of different amounts of phospholipids, cholesterol esters (CEs), triglycerides (TGs), and apolipoprotein A-Is. Our results reveal that the amount of TGs in the vicinity of water molecules in the phospholipid monolayer is 25-50% higher compared to the amount of CEs in a lipid droplet with a mixed core of an equal amount of TG and CE. In addition, the correlation time for the exchange of molecules between the core and the monolayer is significantly longer for TGs compared to CEs. This suggests that the chemical potential of TG is lower in the vicinity of aqueous phase but the free-energy barrier for the translocation between the monolayer and the core is higher compared to CEs. From the point of view of enzymatic modification, this indicates that TG molecules are more accessible from the aqueous phase. Further, our results point out that CE molecules decrease the interfacial tension of HDL-like lipid droplets whereas TG keeps it constant while the amount of phospholipids varies.
|
|
| 5. |
- Laaksonen, Reijo, et al.
(författare)
-
A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle
- 2006
-
Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects.METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo.PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein.CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.
|
|
| 6. |
- Lankinen, Maria A., et al.
(författare)
-
Dietary carbohydrate modification alters serum metabolic profiles in individuals with the metabolic syndrome
- 2010
-
Ingår i: NMCD. Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier. - 0939-4753 .- 1590-3729. ; 20:4, s. 249-57
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Whole-grain cereals and diets with a low glycemic index may protect against the development of type 2 diabetes and heart disease, but the mechanisms are poorly understood. We studied the effect of carbohydrate modification on serum metabolic profiles, including lipids and branched chain amino acids, and dependencies between these and specific gene expression pathways in adipose tissue.METHODS AND RESULTS: Twenty subjects with metabolic syndrome were selected from the larger FUNGENUT study population, randomized either to a diet high in oat and wheat bread and potato (OWP) or rye bread and pasta (RP). Serum metabolomics analyses were performed using ultra-performance liquid chromatography coupled to electrospray ionization mass spectrometry (UPLC/MS), gas chromatography (GC) and UPLC. In the OWP group multiple proinflammatory lysophosphatidylcholines increased, while in the RP group docosahexaenoic acid (DHA 22:6n-3) increased and isoleucine decreased. mRNA expression of stress reactions- and adipose tissue differentiation-related genes were up-regulated in adipose tissue in the OWP group. In the RP group, however, pathways related to stress reactions and insulin signaling and energy metabolism were down-regulated. The lipid profiles had the strongest association with the changes in the adipose tissue differentiation pathway when using the elastic net regression model of the lipidomic profiles on selected pathways.CONCLUSION: Our results suggest that the dietary carbohydrate modification alters the serum metabolic profile, especially in lysoPC species, and may, thus, contribute to proinflammatory processes which in turn promote adverse changes in insulin and glucose metabolism.
|
|
| 7. |
- Marinković, Tijana, et al.
(författare)
-
Integrated model of metabolism and autoimmune response in β-cell death and progression to type 1 diabetes
- 2012
-
Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:12
-
Tidskriftsartikel (refereegranskat)abstract
- Progression to type 1 diabetes is characterized by complex interactions of environmental, metabolic and immune system factors, involving both degenerative pathways leading to loss of pancreatic β-cells as well as protective pathways. The interplay between the degenerative and protective pathways may hold the key to disease outcomes, but no models have so far captured the two together. Here we propose a mathematical framework, an ordinary differential equation (ODE) model, which integrates metabolism and the immune system in early stages of disease process. We hypothesize that depending on the degree of regulation, autoimmunity may also play a protective role in the initial response to stressors. We assume that β-cell destruction follows two paths of loss: degenerative and autoimmune-induced loss. The two paths are mutually competing, leading to termination of the degenerative loss and further to elimination of the stress signal and the autoimmune response, and ultimately stopping the β-cell loss. The model describes well our observations from clinical and non-clinical studies and allows exploration of how the rate of β-cell loss depends on the amplitude and duration of autoimmune response.
|
|
| 8. |
- Niemelä, Perttu S., et al.
(författare)
-
Bioinformatics and computational methods for lipidomics
- 2009
-
Ingår i: Journal of chromatography. B. - : Elsevier. - 1570-0232 .- 1873-376X. ; 877:26, s. 2855-2862
-
Tidskriftsartikel (refereegranskat)abstract
- Large amounts of lipidomics data are rapidly becoming available. However, there is a lack of tools capable of taking the full advantage of the wealth of new information. Lipid bioinformatics is thus an emerging need as well as challenge for lipid research. Lipid concentration changes in biological systems reflect regulation at multiple spatial and dynamic scales, e.g., biochemical reactions in the cells, intercellular lipid trafficking, changes in cell membrane composition, systemic lipid metabolism or lipid oxidation. In order to address the complexity of lipids and their regulation, four areas of bioinformatics need to be developed: (1) data processing and lipid identification, (2) statistical data analysis, (3) pathway analysis, and (4) lipid modeling in systems and biophysical contexts. In this paper we overview the current state of the lipid bioinformatics field as well as suggest few potential new areas of research.
|
|
| 9. |
- Nikkilä, Janne, et al.
(författare)
-
Gender-dependent progression of systemic metabolic states in early childhood
- 2008
-
Ingår i: Molecular Systems Biology. - : Nature Publishing Group. - 1744-4292 .- 1744-4292. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about the human intra-individual metabolic profile changes over an extended period of time. Here, we introduce a novel concept suggesting that children even at a very young age can be categorized in terms of metabolic state as they advance in development. The hidden Markov models were used as a method for discovering the underlying progression in the metabolic state. We applied the methodology to study metabolic trajectories in children between birth and 4 years of age, based on a series of samples selected from a large birth cohort study. We found multiple previously unknown age- and gender-related metabolome changes of potential medical significance. Specifically, we found that the major developmental state differences between girls and boys are attributed to sphingolipids. In addition, we demonstrated the feasibility of state-based alignment of personal metabolic trajectories. We show that children have different development rates at the level of metabolome and thus the state-based approach may be advantageous when applying metabolome profiling in search of markers for subtle (patho)physiological changes.
|
|
| 10. |
- Oresic, Matej, 1967-, et al.
(författare)
-
Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes
- 2013
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 62:9, s. 3268-3274
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies show that children who later progress to type 1 diabetes (T1D) have decreased preautoimmune concentrations of multiple phospholipids as compared with nonprogressors. It is still unclear whether these changes associate with development of β-cell autoimmunity or specifically with clinical T1D. Here, we studied umbilical cord serum lipidome in infants who later developed T1D (N = 33); infants who developed three or four (N = 31) islet autoantibodies, two (N = 31) islet autoantibodies, or one (N = 48) islet autoantibody during the follow-up; and controls (N = 143) matched for sex, HLA-DQB1 genotype, city of birth, and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry. We found that T1D progressors are characterized by a distinct cord blood lipidomic profile that includes reduced major choline-containing phospholipids, including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids that predicted high risk for progression to T1D with an odds ratio of 5.94 (95% CI, 1.07-17.50). Reduction in choline-containing phospholipids in cord blood therefore is specifically associated with progression to T1D but not with development of β-cell autoimmunity in general.
|
|
