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

By Jay D. Horton, Nila A. Shah, J. Warrington, Norma N. Anderson, Sahng-Wook Park, Michael S. Brown, J. Goldstein. Proceedings of the National Academy of Sciences of the United States of America, 2003

1,475 citations recorded by the source corpus.

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 transgenic/knockout approach allows identification of genes whose activities are likely to be controlled directly by one family of transcription factors, in this case the SREBPs.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/db0c9c34dc08a9bc0b9a38995adb150c1f552a60

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Citations in the corpus

mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. (2011, positive): “We ﬁrst determined to what extent rapamycin and Torin1 regulated the mRNA expression of numerous genes that are known to be induced by SREBP-1 and/or SREBP-2, such as fatty acid synthase (FASN), acetyl-CoA carboxylase alpha (ACACA), stearoylCoA-desaturase(SCD1),HMG-CoAreductase(HMGCR), and farnesyl ”
TFOS DEWS II pathophysiology report. (2017, background): “In the second step, the amino terminal fragment, containing the transcription factor, is rapidly released by the site 2 protease and migrates into the cell nucleus where it activates the transcription of genes needed for cholesterol uptake and synthesis as well as those involved with fatty acid meta”
Molecular biology of PCSK9: its role in LDL metabolism. (2007, background): “As reviewed previously, both the LDLR and PCSK9 are transcriptionally regulated by SREBP-2 [4].”
Paternally-induced transgenerational environmental reprogramming of metabolic gene expression in mammals (2010, background): “Genes scored as up in both replicates from Horton et al. (2003) are shown as yellow, genes scored as down are blue.”
Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways (2011, background): “SREBP induces the expression of Insig1, and the INSIG1 protein is stabilized under sterol-rich conditions, creating an autoinhibitory feedback mechanism (Gong et al., 2006; Horton et al., 2003; Yang et al., 2002).”
Mechanisms of Disease: genetic causes of familial hypercholesterolemia (2007, background): “The mechanism by which mutations in PCSK9 cause hypercholesterolemia is not yet fully understood, but PCSK9 is a sterol-regulated gene”
Molecular mediators of hepatic steatosis and liver injury. (2004, neutral): “The critical role of ACC2 in hepatic fatty acid metabolism was revealed in mice that harbored the genetic deletion of the Acc2 gene.”
A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins (2015, positive): “Although SREBP-1 was isolated by virtue of its ability to activate transcription of the LDL receptor gene, we soon found that the protein activates the gene for HMGCoA reductase as well as the genes for all of the enzymes in the cholesterol biosynthetic pathway, thereby allowing cells to synthesize ”