Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels.

Abstract

Hepatocyte nuclear factor (HNF)-4␣ is a transcription factor that plays an important role in regulation of

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

“…ApoCIII is an HNF4α target gene, as demonstrated by in vitro promoter analyses [56,57] and verified by the decreased expression of ApoCIII in a liver HNF4α-deficient mouse model [2,6] and in human patients with mutations in HNF4α [58]. In the present study, HNF4α activated the human ApoCIII promoter in HepG2 hepatoma cells, and to an even greater extent in COS-1 cells, which are devoid of the low level of endogenous HNF4α found in HepG2 cells.…”

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

“…Two non-carrier subjects of the A232D pedigree had triglyceride levels of 1.17 and 1.25 mmol/l, suggesting that triglyceride levels may be lower in subjects with these two GCK mutations. The triglyceride level (mean 0.84 mmol/l) in the 15 MODY2 carriers is similar to that observed in 18 carriers of the RW/MODY1 pedigree (mean 0.80 mmol/l) [2]. In contrast, the triglyceride concentrations were normal in a very large series of primarily French MODY2 patients (mean BMI 22.0) [7].…”

“…This is illustrated by studies of apolipoproteins in different MODY1 pedigrees with various mutations of the gene encoding hepatocyte nuclear factor 4α (HNF4A). The mean plasma triglyceride concentration was significantly lower in 18 subjects (mean BMI 24.0) of the Michigan RW pedigree with the Q268X mutation (mean 0.80 mmol/l) [2] and in six subjects (mean BMI 24.0) from a Swedish family with the K99fsdelAA mutation (mean 0.64 mmol/l) [3] compared with 1.39 and 1.36 mmol/l, respectively, in control groups matched for BMI. The 18 RW subjects also had significantly lower lipoprotein(a) concentrations (mean 0.31 mmol/l) compared with the 24 control subjects (1.16 mmol/l).…”

“…However, there were no significant differences in triglyceride or lipoprotein(a) concentrations between carriers and controls in 42 subjects (mean BMI 25.3) from 11 families with a variety of HNF4A mutations in a large European collection [4], although six subjects (mean BMI 25.2) with the R154X mutations in another study had elevated lipoprotein(a) levels [5]. Various other apolipoprotein fractions (AI, AII, CIII, total HDL-cholesterol) have been reported to be significantly lower in subjects with various HNF4A mutations [2,4].Different mutations in the gene encoding glucokinase (GCK/MODY2) have also been associated with differences in apolipoprotein levels. In 15 German MODY2 carriers (A232D mutation, 12 subjects; V154fsdelTG mutation, three subjects) (mean BMI 24.4), the mean triglyceride concentration was 0.84 mmol/l [6].…”

Analysis of Gene Expression Profile Induced by Hepatocyte Nuclear Factor 4α in Hepatoma Cells Using an Oligonucleotide Microarray

“…Mutation in the HNF-4␣ gene in MODY1 impaired triacylglycerol metabolism and insulin secretion. Shih et al (38) reported that serum levels of ApoAII, ApoCIII, lipoprotein(a), and triacylgylcerol were significantly reduced in diabetic patients with HNF-4␣ mutations compared with these levels in matched diabetic patients. Mice lacking hepatic HNF-4␣ expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triacylglycerol levels (39).…”