Metabolomic analysis of the Hepatocyte Nuclear Factor 1 Alpha knockout mouse

Abstract

Genomic mutations in the transcription factor hepatocyte nuclear factor 1 alpha (HNF1α) result in maturity‐onset diabetes of the young type 3 (MODY3), a form of non‐insulin dependent diabetes mellitus (NIDDM). In addition, Hnf1α was identified as a critical factor in the expression of many transporters of the liver, intestine, and kidney. In order to identify the physiological impact of Hnf1α regulation of transporter proteins, metabolomic analysis was performed on urine from Hnf1α+/+ and Hnf1α −/− using ultra‐performance liquid chromatography (UPLC) coupled with accurate mass determination by time‐of‐flight mass spectrometry (TOFMS). Multivariate analysis revealed clear separation of urinary metabolites between Hnf1α +/+ and Hnf1α −/− mice. Amino acid derived compounds were elevated in the urine of Hnf1α −/− mice suggesting a defect in apical reabsorption in the proximal tubules of the kidney. mRNA expression of members of the imino‐glycine family of transporters was also reduced in Hnf1α −/− mice. In addition to amino acid excretion, steroid hormones associated with adrenal gland function were elevated in the urine of knockout mice. Adrenal glands of Hnf1α −/− were 3‐fold heavier than Hnf1α +/+ and histology showed hyperplasia and reduced lipid content indicating a role for Hnf1α in the endocrine system. Research funded by NIGMS PRAT program and NCI Intramural Research Grants.