Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study.
Biomarkers
HNF1B
MODY
Maturity-onset diabetes of the young
Metabolomics
Pathogenesis
Polycystic kidney disease
Journal
Metabolomics : Official journal of the Metabolomic Society
ISSN: 1573-3890
Titre abrégé: Metabolomics
Pays: United States
ID NLM: 101274889
Informations de publication
Date de publication:
18 02 2022
18 02 2022
Historique:
received:
28
07
2021
accepted:
01
02
2022
entrez:
18
2
2022
pubmed:
19
2
2022
medline:
25
3
2022
Statut:
epublish
Résumé
Patients with hepatocyte nuclear factor-1 beta (HNF1B) mutations present a variable phenotype with two main symptoms: maturity onset diabetes of the young (MODY) and polycystic kidney disease (PKD). Identification of serum metabolites specific for HNF1Bmut and evaluation of their role in disease pathogenesis. We recruited patients with HNF1Bmut (N = 10), HNF1Amut (N = 10), PKD: non-dialyzed and dialyzed (N = 8 and N = 13); and healthy controls (N = 12). Serum fingerprinting was performed by LC-QTOF-MS. Selected metabolite was validated by ELISA (enzyme-linked immunosorbent assay) measurements and then biologically connected with HNF1B by in silico analysis. HepG2 were stimulated with lysophosphatidic acid (LPA) and HNF1B gene was knocked down (kd) by small interfering RNA. Transcriptomic analysis with microarrays and western blot measurements were performed. Serum levels of six metabolites including: arachidonic acid, hydroxyeicosatetraenoic acid, linoleamide and three LPA (18:1, 18:2 and 20:4), had AUC (the area under the curve) > 0.9 (HNF1Bmut vs comparative groups). The increased level of LPA was confirmed by ELISA measurements. In HepG2 LPA is elevated in sera of patients with HNF1Bmut. LPA contributes to the pathogenesis of HNF1B-MODY by affecting Wnt/GSK-3 signaling.
Identifiants
pubmed: 35179657
doi: 10.1007/s11306-022-01873-z
pii: 10.1007/s11306-022-01873-z
pmc: PMC8857088
doi:
Substances chimiques
HNF1B protein, human
0
Lysophospholipids
0
Hepatocyte Nuclear Factor 1-beta
138674-15-4
Glycogen Synthase Kinase 3
EC 2.7.11.26
lysophosphatidic acid
PG6M3969SG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15Informations de copyright
© 2022. The Author(s).
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