Evidence map›Paper›PMID 30518688›Full record

ArticleJCI insight2018

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia.

Irini Manoli, Justin R Sysol, Madeline W Epping, Lina Li, Cindy Wang, Jennifer L Sloan, Alexandra Pass, Jack Gagné, Yiouli P Ktena, Lingli Li and 21 more

Registry-linked trialOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00078078 (Clinical and Basic Investigations of Methylmalonic Acidemia), which is not on this map. Cited by 46 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
46citing papers in PubMed, 1 pooled it
4.2field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00078078 recruitingnot on this map

Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2004Enrolled2,275ConditionsOrganic Acidemia, Methylmalonic Acidemia, Inborn Errors of Metabolism
3 · Its place in the literature

Who cites it

46 citing papers in PubMed, 1 synthesis or guideline pooled it, 83 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors at 13 institutions in 4 countries.

Irini ManoliMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Justin R SysolMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Madeline W EppingMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Lina LiMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Cindy WangMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Jennifer L SloanMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Alexandra PassMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Jack GagnéMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Yiouli P KtenaMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Lingli LiKidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
Niraj S TrivediGenome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Bazoumana OuattaraSherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, Quebec, Canada.
Patricia M ZerfasOffice of Research Services, NIH, Bethesda, Maryland, USA.
Victoria HoffmannOffice of Research Services, NIH, Bethesda, Maryland, USA.
Mones Abu-AsabUltrastructural Pathology Section, Center for Cancer Research, NIH, Bethesda, Maryland, USA.
Maria G TsokosUltrastructural Pathology Section, Center for Cancer Research, NIH, Bethesda, Maryland, USA.
David E KleinerLaboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Caterina GaroneDepartment of Neurology, Columbia University Medical Center, New York, New York, USA.
Kristina Cusmano-OzogDivision of Medical Genetics, Stanford University, Stanford, California, USA.
Gregory M EnnsDivision of Medical Genetics, Stanford University, Stanford, California, USA.
Hilary J VernonMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Hans C AnderssonHayward Genetics Center, Tulane University Medical School, New Orleans, Louisiana, USA.
Stephanie GrunewaldDepartment of Pediatric Metabolic Medicine, Great Ormond Street Hospital for Children Foundation Trust, Institute of Child Health, UCL, London, United Kingdom.
Abdel G ElkahlounGenome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Christiane L GirardSherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, Quebec, Canada.
Jurgen SchnermannKidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
Salvatore DiMauroDepartment of Neurology, Columbia University Medical Center, New York, New York, USA.
Eva Andres-MateosGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
Luk H VandenbergheGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
Randy J ChandlerMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Charles P VendittiMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
National Human Genome Research Institute · USAgriculture and Agri-Food Canada · CACenter for Cancer Research · USColumbia University Irving Medical Center · USOffice of Research Services · USStanford University · USBroad Institute · USGreat Ormond Street Hospital for Children NHS Foundation Trust · GBJohns Hopkins University · USMassachusetts Eye and Ear Infirmary · USNational Cancer Institute · USNational Institute of Diabetes and Digestive and Kidney Diseases · USTulane University · US

Funding

Investigations of Methylmalonic Acidemia and Related DisordersZIAHG200318 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI VENDITTI, CHARLES P · 2009 to 2025
$29.7M
Postmortem PathologyZICBC010685 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI KLEINER, DAVID ERWIN · 2009 to 2025
$14.3M
NHGRI/DIR Microarray CoreZICHG200365 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI ELKAHLOUN, ABDEL · 2011 to 2025
$9.0M
Metabolic Studies in Disorders of Branch Chain Amino Acid MetabolismK08HD073492 · NICHD · JOHNS HOPKINS UNIVERSITY · PI VERNON, HILARY · 2012 to 2016
$684k
Intramural NIH HHS ZIA HG200318NICHD NIH HHS K08 HD073492
6 · The paper itself

Abstract

Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.

Indexed as

HormesisStress, PhysiologicalAmino Acid Metabolism, Inborn ErrorsAnimalsBiomarkersDisease Models, AnimalFemaleFibroblast Growth FactorsGenetic TherapyHumansKidney DiseasesLiverLiver TransplantationMaleMethylmalonyl-CoA MutaseMiceBiomarkersfibroblast growth factor 21Fibroblast Growth FactorsMethylmalonyl-CoA MutaseGene therapyGeneticsIntermediary metabolismMetabolismMitochondria

Identifiers

PMID30518688
PMCPMC6328030
OpenAlexW2902012561

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.