TY - JOUR
T1 - Regulation of Apolipoprotein M Gene Expression by MODY3 Gene Hepatocyte Nuclear Factor-1α
T2 - Haploinsufficiency Is Associated with Reduced Serum Apolipoprotein M Levels
AU - Richter, Symi
AU - Shih, David Q.
AU - Pearson, Ewan R.
AU - Wolfrum, Christian
AU - Fajans, Stefan S.
AU - Hattersley, Andrew T.
AU - Stoffel, Markus
PY - 2003/12
Y1 - 2003/12
N2 - 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.
AB - 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.
KW - apoM, apolipoprotein M
KW - EMSA, electrophoretic mobility shift assay
KW - HNF, hepatocyte nuclear factor
KW - MODY, maturity-onset diabetes of the young
UR - http://www.scopus.com/inward/record.url?scp=0344412888&partnerID=8YFLogxK
U2 - 10.2337/diabetes.52.12.2989
DO - 10.2337/diabetes.52.12.2989
M3 - Article
C2 - 14633861
AN - SCOPUS:0344412888
VL - 52
SP - 2989
EP - 2995
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -