68e07f8a-7ace-499f-b1e3-dde33f063c00
title
Single nucleotide polymorphism ( -468 Gly to A ) at the promoter region of  SREBP-1c  associates with genetic defect of fructose-induced hepatic lipogenesis [corrected].
db919dbc-5fdd-4026-96da-fe4e0793aab3
abstract
To evaluate the genetic susceptibility to metabolic disorders induced by high fructose diet, we investigated the metabolic characteristics in 10 strains of inbred mice and found that they were separated into CBA and DBA groups according to the response to high fructose diet. The hepatic mRNA expression of the  sterol regulatory element-binding protein-1 (SREBP-1)  in CBA/JN was remarkably enhanced by high fructose diet but not in DBA/2N. Similar results were observed in primary hepatocytes after exposure to fructose. The nucleotide sequence at -468 bp from the putative starting point of the  SREBP-1c  gene was adenine in the DBA group while it was guanine in the CBA group. In hepatocytes from CBA/JN, the activity of CBA- SREBP-1c  promoter was significantly increased by 2.4- and 2.2-fold, in response to 30 mm fructose or 10 nm insulin, respectively, whereas the activity of DBA- SREBP-1c  promoter responded to insulin but not to fructose. In hepatocytes from DBA/2N, both types of  SREBP-1c  promoter activities in response to  insulin  were attenuated. Furthermore, electrophoretic mobility shift assay revealed an unidentified nuclear protein bound to the oligonucleotides made from the region between -453 to -480 bp of the  SREBP-1c  promoter of CBA/JN but not to the probe from DBA/2N. Thus, in DBA/2N, the reduced mRNA expression of SREBP-1 after fructose refeeding appeared to associate with two independent mechanisms, 1). loss of binding of unidentified proteins to the region between -453 to -480 bp of the  SREBP-1c  promoter and 2). impaired  insulin  stimulation of  SREBP-1c  promoter activity.