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Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study
Introduction 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). Objectives Identification of serum metabolites specific for HNF1B mut and evaluation o...
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Published in: | Metabolomics 2022-03, Vol.18 (3), p.15-15, Article 15 |
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Main Authors: | , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | Introduction
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).
Objectives
Identification of serum metabolites specific for
HNF1B
mut and evaluation of their role in disease pathogenesis.
Methods
We recruited patients with
HNF1B
mut (N = 10),
HNF1A
mut (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.
Results
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 (
HNF1B
mut vs comparative groups). The increased level of LPA was confirmed by ELISA measurements. In HepG2
HNF1Bkd
cells LPA stimulation lead to downregulation of many pathways associated with cell cycle, lipid metabolism, and upregulation of steroid hormone metabolism and Wnt signaling. Also, increased intracellular protein level of autotaxin was detected in the cells. GSK-3alpha/beta protein level and its phosphorylated ratio were differentially affected by LPA stimulation in
HNF1B
kd and control cells.
Conclusions
LPA is elevated in sera of patients with
HNF1B
mut. LPA contributes to the pathogenesis of
HNF1B
-MODY by affecting Wnt/GSK-3 signaling. |
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ISSN: | 1573-3882 1573-3890 |
DOI: | 10.1007/s11306-022-01873-z |