Genotype/phenotype relationships in HNF-4α/MODY1 -: Haploinsufficiency is associated with reduced apolipoprotein(AII), apolipoprotein(CIII), lipoprotein(a), and triglyceride levels
Genotype/phenotype relationships in HNF-4α/MODY1 -: Haploinsufficiency is associated with reduced apolipoprotein(AII), apolipoprotein(CIII), lipoprotein(a), and triglyceride levels
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DOI：
10.2337/diabetes.49.5.832
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发表时间：
2000-05-01
期刊：
影响因子：
7.7
通讯作者：
Stoffel, M
中科院分区：
文献类型：
--
作者：
Shih, DQ;Dansky, HM;Stoffel, M
肝细胞核因子（HNF）-4 α是一种转录因子，在胰腺β细胞和肝脏中的基因表达调控中起重要作用。HNF-4 α基因中的杂合突变导致青年1型成熟型糖尿病（MODY 1），其特征是胰腺β细胞缺乏胰岛素分泌。HNF-4 α是肝脏中表达的许多基因的主要转录调节因子。然而，在HNF-4 α突变的个体中没有发现肝脏缺陷。在这项研究中，我们鉴定了主要在肝脏中表达的HNF-4 α靶基因，包括α 1-抗胰蛋白酶、α 1-抗胰凝乳蛋白酶、α-胎儿蛋白、血浆铜蓝蛋白、IGF结合蛋白1、转铁蛋白、载脂蛋白（AI）[apo（AI）]、apo（AII）、apo（B）和apo（CIII）。在HNF-4 α/MODY 1 RW家系的24名成员中测量这些蛋白质和Lp（a）和甘油三酯的血清水平（Q268 X突变），包括12例HNF-4 α突变的糖尿病患者（D-HNF 4（+/-）），6例HNF-4 α突变的非糖尿病受试者（N-HNF 4（+/-））、6名正常亲属（N-HNF 4（+/+））、6名无关的正常匹配对照受试者（N-HNF 4（+/+））和12名匹配的糖尿病（非MODY 1 -5）患者（D-HNF 4（+/+））。HNF 4（+/-）受试者的血清载脂蛋白（AII）、载脂蛋白（CIII）、脂蛋白（a）[Lp（a）]和甘油三酯水平显著降低（分别为26.9、19.8、12.1和72.1 mg/dl），与HNF 4（+/+）受试者相比（分别为37.4、26.5、45.2和124.2 mg/dl）（分别为P = 0.00001、P = 0.01、P = 0.00006和P = 0.000003）。当比较D-HNF 4（+/-）与N-HNF 4（+/-）或D-HNF 4（+/+）与N-HNF 4（+/+）受试者的载脂蛋白（AII）、载脂蛋白（CIII）、Lp（a）和甘油三酯水平时，未发现这种降低，这表明HNF-4 α单倍不足而非高血糖是血清蛋白和甘油三酯浓度降低的主要原因。此外，我们确定，除了HNF-4 α以外的遗传或环境修饰剂似乎不会导致观察到的HNF-4 α调节的血清蛋白的减少。这项研究表明，杂合HNF-4 α突变导致肝特异性蛋白的HNF-4 α依赖性肝细胞分泌缺陷。
Hepatocyte nuclear factor (HNF)-4 alpha is a transcription factor that plays an important role in regulation of gene expression in pancreatic beta-cells and in the liver. Heterozygous mutations in the HNF-4 alpha gene are responsible for maturity-onset diabetes of the young 1 (MODY1), which is characterized by pancreatic beta-cell-deficient insulin secretion. HNF-4 alpha is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-4 alpha mutations. In this study we have identified HNF-4 alpha target genes that are mainly expressed in the liver, including alpha 1-antitrypsin, alpha 1-antichymotrypsin, alpha-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-4 alpha/MODY1 RW pedigree (Q268X mutation), including 12 diabetic patients with HNF-4 alpha mutations (D-HNF4(+/-)), 6 nondiabetic subjects with HNF-4 alpha 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-4 alpha 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-4 alpha do not appear to contribute to the observed decrease of HNF-4 alpha-regulated serum proteins. This study demonstrates that a heterozygous HNF-4 alpha mutation lends to an HNF-4 alpha-dependent hepatocyte secretory defect of liver-specific proteins.