Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels.

Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Research Abstract Details 

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Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Abstract Text:

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

Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Publishing Authors By Initials

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Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Diabetes

VOLUME: 52

Page Numbers: 2989-95

Journal Abbreviation: Diabetes

ISSN: 0012-1797

DAY: 11

MONTH: Dec

YEAR: 2003

Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Information

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LANGUAGE: eng

NlmUniqueID: 372763

Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Keywords Mesh Terms:

KEYWORDS: Transcription Factors

MESH TERMS: physiology

Chemical & Substance for Abstract: Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Information

Substance Name: Hepatocyte Nuclear Factor 1-beta

Registry Number: 138674-15-4

Grant and Affiliation Information for Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels.

AFFILIATION: Laboratory of Metabolic Diseases, Rockefeller University, New York, New York 10021, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: R01DK55033-01

ACRONYM: DK

MEDLINETA: Diabetes

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