ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 S15.5 | DOI: 10.1530/endoabs.63.S15.5

Lysophosphatidic acid in pathogenesis of HNF1B-MODY syndrome

Beata Małachowska


Background: HNF1B-MODY is a rare autosomal dominant monogenic form of diabetes coexisting with kidney abnormalities.

Objectives: Identification of altered serum metabolites among HNF1B-MODY patients and investigating its function in syndrome pathogenesis.

Methods: We recruited patients with HNF1B-MODY (N=10), HNF1A-MODY (N=10), polycystic kidney disease: non-dialyzed and dialyzed (N=8 and N=13 respectively) and healthy controls (N=12). Serum samples were fingerprinted by LC/MS. Observed metabolic changes were validated. A HepG2 cell line was used in order to study in vitro the cellular effect of selected serum metabolite stimulation.

Results: From serum metabolomics fingerprinting we identified eight metabolites that had convergent fold change for comparison of HNF1B-MODY versus all other groups. Three of them were lysophosphatidic acid species (LPAs: 18:1, 18:2, 20:4) that proved to be the best biomarkers for HNF1B-MODY (Area under ROC curve 1.00 (95%CI 0.91–1.00); 1.00 (95%CI 0.91–1.00); 0.92 (95%CI 0.80–0.98) respectively). On a second set of samples we confirmed elevated levels of LPA among HNF1B-MODY patients (P=0.0063). The main enzyme producing serum LPA – autotaxin – was down-regulated in sera of HNF1A- vs HNF1B-MODY patients (P=0.0173) but did not differ between HNF1B and other groups (all P values >0.84). Upon LPA stimulation of human hepatocytes with silenced HNF1B the downregulation of autotaxin expression was observed. In the absence of functional Hnf1b, the stimulatory effect of LPA on the Wnt pathway was disrupted and reversed, with LPA stimulation leading to a decrease of phospho-GSK-3a/b protein (P=0.0169).

Conclusions: An important lipid mediatory compound – LPA was found to be elevated in serum of patients with HNF1B-MODY. LPA can be involved with pathogenesis of HNF1B-MODY syndrome via the disruption of LPA-mediated regulation of Wnt pathway.

The study was funded by the PRELUDIUM grant (2016/21/N/NZ5/01448) of the National Science Center, Poland and by JDRF-ISPAD Research Fellowship Award 2017.

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