Sterol regulatory element binding protein‐1a knock‐out mice have an impaired response to fasting and refeeding.

Abstract

Sterol regulatory element binding proteins (SREBPs) regulates the transcription of key enzymes in fatty acid, triacylglycerol, and cholesterol synthesis. There are three SREBP-isoforms derived from two genes, SREBP-1 and SREBP-2. SREBP–1a and –1c, encoded by a single gene, are produced through the use of alternative promoters producing transcripts with unique first exons. Gene trapping targeted to the unique first intron of SREBP-1a was used to generate SREBP-1a−/− mice. To begin to evaluate the functional role of SREBP-1a in lipid metabolism, SREBP-1a−/−and wild-type mice were subjected to a fasting and high carbohydrate refeeding regiment. Plasma nonesterified fatty acids did not differ between genotypes in the fed state, but showed a blunted response to fasting and refeeding in the SREBP-1a−/− mice. Plasma triacylglycerol and total cholesterol did not differ between genotypes in the fed or fasted states, but were significantly elevated in the SREBP-1a−/− mice in the refed state. SREBP-1c and -2 gene expression did not differ between genotypes. However, there were significant differences in expression of SREBP target genes as well as differences in SREBP binding to target gene promoters through chromatin immunoprecipation (ChIP) assay. This study demonstrates the importance of SREBP-1a in regulating lipid metabolism.