Regulatory SNP in the RBP4 gene modified the expression in adipocytes and associated with BMI.
Retinol-binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte-derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single-nucleotide polymorphism (SNP -803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in -803GA heterozygotes showed that the minor allele-linked haplotype-derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9-cis-retinoic acid (RA) and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the -803G>A SNP modulate the affinity against unidentified DNA-binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.
Division of Human Genetics, Center for Community Medicine, Jichi Medical University, Tochigi, Japan.
Lkhagvasuren
L
Munkhtulga
Shuichi
S
Nagashima
Kazuhiro
K
Nakayama
Nanami
N
Utsumi
Yoshiko
Y
Yanagisawa
Takaya
T
Gotoh
Toshinori
T
Omi
Maki
M
Kumada
Khadbaatar
K
Zolzaya
Tserenkhuu
T
Lkhagvasuren
Yasuo
Y
Kagawa
Hiroyuki
H
Fujiwara
Yoshinori
Y
Hosoya
Masanobu
M
Hyodo
Hisanaga
H
Horie
Masayuki
M
Kojima
Shun
S
Ishibashi
Sadahiko
S
Iwamoto
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D015992:Body Mass Index; D002460:Cell Line; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D018579:Patient Selection; D000077205:Pioglitazone; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma; D045162:Thiazolidinediones; D000077205:Pioglitazone