| Abstract: |
Hepatocyte nuclear factor (HNF)-4α is a transcription factor that plays an important role in regulation of gene expression in pancreatic β-cells and in the liver. Heterozygous mutations in the HNF-4α gene are responsible for maturity-onset diabetes of the young 1 (MODY1), which is characterized by pancreatic β-cell-deficient insulin secretion. HNF-4α is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-4α mutations. In this study, we have identified HNF-4α target genes that are mainly expressed in the liver, including α1-antitrypsin, α1-antichymotrypsin, α-fetal protein, ceruloplasmin, IGF binding protein 1, transferrin, apolipoprotein(AI) [apo(AI)], apo(AII), apo(B), and apo(CIII). Serum levels of these proteins and Lp(a) and triglycerides were measured in 24 members of the HNF-4α/MODY1 RW pedigree (Q268X mutation), including 12 diabetic patients with HNF-4α mutations (D-HNF(+/-)), 6 nondiabetic subjects with HNF-4α mutations (N-HNF4(+/-)), 6 normal relatives (N-HNF4(+/+)), 6 unrelated normal matched control subjects (N-HNF4(+/+)), and 12 matched diabetic (non-MODY1-5) patients (D-HNF4(+/+)). Serum levels of apo(AII), apo(CIII), lipoprotein(a) [Lp(a)], and triglyceride were significantly reduced in HNF4(+/-) subjects (26.9, 19.8, 12.1, and 72.1 mg/dl, respectively) compared with HNF4(+/+) subjects (37.4, 26.5, 45.2, and 124.2 mg/dl, respectively) (P = 0.00001, P = 0.01, P = 0.00006, and P = 0.000003, respectively). This reduction was not found when apo(AII), apo(CIII), Lp(a), and triglyceride levels were compared in D-HNF4(+/-) versus N-HNF4(+/-) or in D-HNF4(+/+) versus N-HNF4(+/+) subjects, which indicates that HNF-4α haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum protein and triglyceride concentrations. Furthermore, we determined that genetic or environmental modifiers other than HNF-4α do not appear to contribute to the observed decrease of HNF-4α-regulated serum proteins. This study demonstrates that a heterozygous HNF-4α mutation leads to an HNF4α-dependent hepatocyte secretory defect of liver-specific proteins. |
