Premium
Functional analysis of promoter variants in the microsomal triglyceride transfer protein ( MTTP ) gene
Author(s) -
Rubin Diana,
SchneiderMuntau Alexandra,
Klapper Maja,
Nitz Inke,
Helwig Ulf,
Fölsch Ulrich R.,
Schrezenmeir Jürgen,
Döring Frank
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20615
Subject(s) - microsomal triglyceride transfer protein , biology , haplotype , mutant , apolipoprotein b , promoter , gene , genetics , microbiology and biotechnology , lipoprotein , cholesterol , allele , gene expression , endocrinology , very low density lipoprotein
The microsomal triglyceride transfer protein ( MTTP ) is required for the assembly and secretion of apolipoprotein B (apoB)‐containing lipoproteins from the intestine and liver. According to this function, polymorphic sites in the MTTP gene showed associations to low‐density lipoprotein (LDL) cholesterol and related traits of the metabolic syndrome. Here we studied the functional impact of common MTTP promoter polymorphisms rs1800804:T>C (−164T>C), rs1800803:A>T (−400A>T), and rs1800591:G>T (−493G>T) using gene‐reporter assays in intestinal Caco‐2 and liver Huh‐7 cells. Significant results were obtained in Huh‐7 cells. The common MTTP promoter haplotype −164T/−400A/−493G showed about two‐fold lower activity than the rare haplotype −164C/−400T/−493T. MTTP promoter mutant constructs −164T/−400A/−493T and −164T/−400T/−493T exhibited similar activity than the common haplotype. Activities of mutants −164C/−400A/−493G and −164C/−400A/−493T resembled the rare MTTP promoter haplotype. Electrophoretic mobility shift assays (EMSAs) revealed higher binding capacity of the transcriptional factor Sterol regulatory element binding protein1a (SREBP1a) to the −164T probe in comparison to the −164C probe. In conclusion, our study indicates that the polymorphism −164T>C mediates different activities of common MTTP promoter haplotypes via SREBP1a. This suggested that the already described SREBP‐dependent modulation of MTTP expression by diet is more effective in −164T than in −164C carriers. Hum Mutat 29(1), 123–129, 2008. © 2007 Wiley‐Liss, Inc.