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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) &gt; 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.

Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study