Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes

Abstract

The synthesis of fatty acids and cholesterol, the building blocks of membranes, is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs as a result of gene knockout of SREBP cleavage-activating protein (SCAP), a protein required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. A total of 1,003 genes showed statistically significant increased expression in livers of transgenic SREBP-1a mice, 505 increased in livers of transgenic SREBP-2 mice, and 343 showed decreased expression in Scap ؊͞؊ livers. A subset of 33 genes met the stringent combinatorial criteria of induction in both SREBP transgenics and decreased expression in SCAP-deficient mice. Of these 33 genes, 13 were previously identified as direct targets of SREBP action. Of the remaining 20 genes, 13 encode enzymes or carrier proteins involved in cholesterol metabolism, 3 participate in fatty acid metabolism, and 4 have no known connection to lipid metabolism. Through application of stringent combinatorial criteria, the transgenic͞knockout approach allows identification of genes whose activities are likely to be controlled directly by one family of transcription factors, in this case the SREBPs.

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

“…SREBP-2 is considered to be the global regulator of cholesterol synthesis (Horton et al, 2003) and is known to increase HMGCR transcripition (Sakakura et al, 2001). Our results are in contrast to a previous study where no difference between the two alleles was reported (Porcellini et al, 2007).…”

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

“…2F). Furthermore, SREBP_Direct_Hepatic_Target gene signature (Horton et al ., 2003), which is increased by in vivo overexpression of nuclear form SREBP‐1a (nSREBP‐1a) or nuclear form SREBP‐1 (nSREBP‐2), and decreased by in vivo SCAP knockout, was less enriched in cells with HDGF knockdown (Fig. 2G).…”

“…Gene sets were from msigdb _v6.1 (Broad Institute) and manually curated from studies (Horton et al ., 2003; Reed et al ., 2008; Rome et al ., 2008). Differentially expressed genes were rank‐ordered by fold change in expression.…”

Transcriptional regulation of acetyl-CoA carboxylase α isoforms in dairy ewes during conjugated linoleic acid induced milk fat depression

“…Interestingly, SREBP1, that it is considered a global regulator of lipid synthesis (Eberlé et al, 2004), had a similar response to the ACC-α PIII transcripts in the mammary gland, whereas in adipose tissue had a similar response to ACC-α PI transcripts and FASN. SREBP1 regulates enzymes which synthesize FA and cholesterol from precursor molecules (Horton et al, 2003;Goldstein et al, 2006) and SREBP1 is a major regulator of mammary de novo FA synthesis and the response to dietary factors that modify milk fat in mouse (Anderson et al, 2007) and cow (Harvatine and Bauman, 2006).…”