Sort by: Order: Results:

Now showing items 1-8 of 8
  • Lamichhane, Santosh; Ahonen, Linda; Dyrlund, Thomas Sparholt; Dickens, Alex M.; Siljander, Heli; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2019)
    Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
  • Grabon, Aby; Orlowski, Adam; Tripathi, Ashutosh; Vuorio, Joni; Javanainen, Matti; Rog, Tomasz; Lönnfors, Max; McDermott, Mark I.; Siebert, Garland; Somerharju, Pentti; Vattulainen, Ilpo; Bankaitis, Vytas A. (2017)
    Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITP alpha, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITP alpha lipid exchange cycle: (i) interaction of PITP alpha with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP alpha to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITP alpha; (iv) the trajectory of PtdIns or PtdCho into and through the lipidbinding pocket is chaperoned by sets of PITP alpha residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITP alpha PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family.
  • Zhang, Lu; Diaz-Diaz, Norberto; Zarringhalam, Kourosh; Hermansson, Martin; Somerharju, Pentti; Chuang, Jeffrey (2012)
  • Jia, Qiong; Han, Yi; Huang, Pin; Woodward, Nicholas C.; Gukasyan, Janet; Kettunen, Johannes; Ala-Korpela, Mika; Anufrieva, Olga; Wang, Qin; Perola, Markus; Raitakari, Olli; Lehtimaki, Terho; Viikari, Jorma; Jarvelin, Marjo-Riitta; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L.; Fiehn, Oliver; Wang, Zeneng; Tang, W. H. Wilson; Hazen, Stanley L.; Hartiala, Jaana A.; Allayee, Hooman (2019)
    Background-Recent studies have revealed sexually dimorphic associations between the carbamoyl-phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease (CAD) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl-phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results-We sought to identify additional genetic determinants of circulating glycine levels by carrying out a metaanalysis of genome-wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine-associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism (ACADM, PHGDH, COX1 8-ADAMTS3, PSPH, TRIB 1 , PTPRD, and ABO). Glycine-raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD. However, these effects could not be attributed directly to glycine because of associations with other CAD-related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity-related traits. Conclusions-These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.
  • Luukkonen, Panu K.; Tukiainen, Taru; Juuti, Anne; Sammalkorpi, Henna; Haridas, P. A. Nidhina; Niemelä, Onni; Arola, Johanna; Orho-Melander, Marju; Hakkarainen, Antti; Kovanen, Petri T.; Dwivedi, Om; Groop, Leif; Hodson, Leanne; Gastaldelli, Amalia; Hyötyläinen, Tuulia; Oresic, Matej; Yki-Järvinen, Hannele (2020)
    Carriers of the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [ONLI and adipose tissue lipolysis [ATL] using (H2O)-H-2 and H-2-glycerol) and insulin sensitivity using H-3-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, ONL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.
  • Pessa-Morikawa, Tiina; Husso, Aleksi; Kärkkäinen, Olli; Koistinen, Ville; Hanhineva, Kati; Iivanainen, Antti; Niku, Mikael (2022)
    Background The maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. To reveal the spectrum of these molecular mediators of the earliest host-microbe interactions, we compared placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. Results One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. More than half of these were more abundant in the SPF organs, suggesting their microbial origin or a metabolic response of the host to the presence of microbes. The clearest separation was observed in the placenta, but most of the molecular features showed significantly different levels also in the fetal intestine and/or brain. Metabolites that were detected in lower amounts in the GF fetal organs included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid, were also less abundant in the absence of microbiota. Ninety-nine molecular features were detected only in the SPF mice. We also observed several molecular features which were more abundant in the GF mice, possibly representing precursors of microbial metabolites or indicators of a metabolic response to the absence of microbiota. Conclusions The maternal microbiota has a profound impact on the fetal metabolome. Our observations suggest the existence of a multitude of yet unidentified microbially modified metabolites which pass through the placenta into the fetus and potentially influence fetal development.
  • Koistinen, Ville M.; Mattila, Outi; Katina, Kati; Poutanen, Kaisa; Aura, Anna-Marja; Hanhineva, Kati (2018)
    Sourdough fermentation by lactic acid bacteria is commonly used in bread baking, affecting several attributes of the final product. We analyzed whole-grain wheat and rye breads and doughs prepared with baker's yeast or a sourdough starter including Candida milleri, Lactobacillus brevis and Lactobacillus plantarum using non-targeted metabolic profiling utilizing LC-QTOF-MS. The aim was to determine the fermentation-induced changes in metabolites potentially contributing to the health-promoting properties of whole-grain wheat and rye. Overall, we identified 118 compounds with significantly increased levels in sourdough, including branched-chain amino acids (BCAAs) and their metabolites, small peptides with high proportion of BCAAs, microbial metabolites of phenolic acids and several other potentially bioactive compounds. We also identified 69 compounds with significantly decreased levels, including phenolic acid precursors, nucleosides, and nucleobases. Intensive sourdough fermentation had a higher impact on the metabolite profile of whole-grain rye compared to milder whole-grain wheat sourdough fermentation. We hypothesize that the increased amount of BCAAs and potentially bioactive small peptides may contribute to the insulin response of rye bread, and in more general, the overall protective effect against T2DM and CVD.
  • Jääskeläinen, Tiina; Kärkkäinen, Olli; Heinonen, Seppo; Hanhineva, Kati; Laivuori, Hannele (2022)
    Only a few studies have explored the role of microbiota-dependent metabolite trimethylamine N-oxide (TMAO) in non-complicated pregnancy and in pre-eclampsia (PE). We enrolled 139 PE and 29 healthy pregnant women in a nested case control study. We hypothesized that elevated levels of circulating TMAO and its precursors choline and glycine betaine in the late second or in third trimester might contribute to the PE and are associated with the onset of the disease and clinical features such as elevated blood pressure. The association with a few available lifestyle factors (use of fish and physical activity) was also evaluated. In contrast with the previous findings, there was no difference in TMAO concentration between PE and healthy women. In addition, TMAO concentration was not associated with any of the PE related clinical features, angiogenic or inflammatory markers. In future, it is crucial to obtain longitudinal data on TMAO in both non-complicated and in PE pregnancies before we could have more detailed understanding of TMAO.