Browsing by Subject "FGF21"

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  • Forsström, Saara; Jackson, Christopher B.; Carroll, Christopher J.; Kuronen, Mervi; Pirinen, Eija; Pradhan, Swagat; Marmyleva, Anastasiia; Auranen, Mari; Kleine, Iida-Marja; Khan, Nahid A.; Roivainen, Anne; Marjamäki, Paivi; Liljenbäck, Heidi; Wang, Liya; Battersby, Brendan J.; Richter, Uwe; Velagapudi, Vidya; Nikkanen, Joni; Euro, Liliya; Suomalainen, Anu (2019)
    Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.
  • McKeown, Nicola M.; Dashti, Hassan S.; Ma, Jiantao; Haslam, Danielle E.; Kiefte-de Jong, Jessica C.; Smith, Caren E.; Tanaka, Toshiko; Graff, Mariaelisa; Lemaitre, Rozenn N.; Rybin, Denis; Sonestedt, Emily; Frazier-Wood, Alexis C.; Mook-Kanamori, Dennis O.; Li, Yanping; Wang, Carol A.; Leermakers, Elisabeth T. M.; Mikkilä, Vera; Young, Kristin L.; Mukamal, Kenneth J.; Cupples, L. Adrienne; Schulz, Christina-Alexandra; Chen, Tzu-An; Li-Gao, Ruifang; Huang, Tao; Oddy, Wendy H.; Raitakari, Olli; Rice, Kenneth; Meigs, James B.; Ericson, Ulrika; Steffen, Lyn M.; Rosendaal, Frits R.; Hofman, Albert; Kähönen, Mika; Psaty, Bruce M.; Brunkwall, Louise; Uitterlinden, Andre G.; Viikari, Jorma; Siscovick, David S.; Seppälä, Ilkka; North, Kari E.; Mozaffarian, Dariush; Dupuis, Josee; Orho-Melander, Marju; Rich, Stephen S.; Mutsert, Renee de; Qi, Lu; Pennell, Craig E.; Franco, Oscar H.; Lehtimaki, Terho; Herman, Mark A. (2018)
    Aims/hypothesis Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Methods Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. Results In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (beta +/- SE 0.014 +/- 0.004 [mmol/l], p = 1.5 x 10(-3)) and higher fasting insulin (0.030 +/- 0.005 [log(e) pmol/l], p = 2.0 x 10(-10)). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the beta-Klotho (KLB) locus on fasting insulin (0.030 +/- 0.011 log(e) pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. Conclusions/interpretation In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.
  • Kleine, Iida-Marja (Helsingin yliopisto, 2018)
    This study investigates the metabolic consequences of a biomarker for mitochondrial myopathies, using the mouse as a model organism. The studied biomarker is fibroblast growth factor 21 (FGF21), which is secreted in high amounts from the diseased muscle tissue. It is an endocrine hormone that regulates lipid metabolism, and in healthy individuals it is mainly secreted from the liver. I utilized skeletal muscle samples from mice that were either wild type or had a mitochondrial myopathy, both with or without a whole-body knockout of FGF21. I analysed a data set from a targeted metabolomic experiment conducted on the skeletal muscle samples. The experiment was performed by our collaborator Vidya Velagapudi. Additionally I measured protein and mRNA expression of selected enzymes from the muscle samples. This study shows, that the cytokine FGF21 contributes to the disease progression of mitochondrial myopathy. The aspects of pathophysiology it regulates were all found to center on the metabolic pathway of one carbon (1C) metabolism. Serine de novo synthesis shuttles glucose carbons into 1C metabolism. The transsulfuration pathway produces glutathione using carbon units from the 1C pathway. The results of this study show, that FGF21 mediates the upregulation of alternative carbon donors in one carbon metabolism, especially serine biosynthesis, and the elevated utilisation of carbon units in the transsulfuration pathway. Not all of the metabolic changes characteristic of mitochondrial myopathy were affected by FGF21, e.g. the upregulation of acyl carnitines seen in mitochondrial myopathy was not affected by the knock-out of FGF21.