Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1α

Abstract

Hepatocyte nuclear factor-1a (HNF-1α) is a transcription factor that plays an important role in regulation of gene expression in pancreatic β-cells, intestine, kidney, and liver. Heterozygous mutations in the HNF-1α gene are responsible for maturity-onset diabetes of the young (MODY3), which is characterized by pancreatic β-cell–deficient insulin secretion. HNF-1α is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-1α mutations. In this study, we show that Hnf-1α is a potent transcriptional activator of the gene encoding apolipoprotein M (apoM), a lipoprotein that is associated with the HDL particle. Mutant Hnf-1α−/− mice completely lack expression of apoM in the liver and the kidney. Serum apoM levels in Hnf-1α+/− mice are reduced ∼50% compared with wild-type animals and are absent in the HDL and HDLc fractions of Hnf-1α−/−. We analyzed the apoM promoter and identified a conserved HNF-1 binding site. We show that Hnf-1α is a potent activator of the apoM promoter, that a specific mutation in the HNF-1 binding site abolished transcriptional activation of the apoM gene, and that Hnf-1α protein can bind to the Hnf-1 binding site of the apoM promoter in vitro. To investigate whether patients with mutations in HNF-1α mutations (MODY3) have reduced serum apoM levels, we measured apoM levels in the serum of nine HNF-1α/MODY3 patients, nine normal matched control subjects (HNF-1α+/+), and nine HNF-4α/MODY1 subjects. Serum levels of apoM were decreased in HNF-1α/MODY3 subjects when compared with control subjects (P < 0.02) as well as with HNF-4α/MODY1 subjects, indicating that HNF-1α haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum apoM protein concentrations. This study demonstrates that HNF-1α is required for apoM expression in vivo and that heterozygous HNF-1α mutations lead to an HNF-1α–dependent impairment of apoM expression. ApoM levels may be a useful serum marker for the identification of MODY3 patients.