Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewRegulation of gene expression by SREBP and SCAP
Introduction
In the 1950s and 1960s, a series of elegant studies carried out in many laboratories including those of K. Bloch, F. Lynen, H. Rilling, H. Rudney, G. Schroepfer, V. Rodwell, J. Cornforth and G. Popják, began to decipher the enzymatic reactions that were necessary for the biosynthesis of cholesterol from acetate (reviewed in [1]). In 1953, Gould et al. provided one of the earliest examples for feedback repression in mammals when they reported that the hepatic synthesis of cholesterol decreased when dogs were fed excess dietary cholesterol [2]. These early studies set the stage for another series of classic investigations that utilized molecular and cell biology to identify and characterize the endocytic pathway involved in the cellular uptake of cholesterol-rich LDL [3], [4] and the subsequent repression of HMG-CoA reductase and cholesterol synthesis [3], [4], [5]. In this review, we propose to describe recent studies that have led to our current understanding of the mechanism involved in the repression of gene expression by cholesterol/oxysterols. As detailed below, these studies led to the identification of a family of transcription factors that play a central role in the regulation of lipid and carbohydrate metabolism. The reader is referred to a number of recent reviews that have been published on this topic [3], [5], [6], [7].
The current data indicate that the active molecule responsible for the repression of cholesterol synthesis is probably not cholesterol per se, but an oxysterol derived from oxidation of the sterol moiety (Fig. 1). Fig. 1 also indicates that oxysterols can function as feed-forward ligands that bind to and activate the nuclear hormone receptors LXRα and LXRβ [8]. Target genes that are known to be transcriptionally activated by LXR are currently limited to Cyp7a, CETP, ABCA1 and ABCG1 [9], [10], [11], [12]. Recent studies have demonstrated that conversion of cholesterol to bile acids or pregnenolone produces ligands that function to activate FXR [13], [14], [15], or PXR [16], respectively. Cholesterol is also a precursor of estrogen, testosterone, aldosterone and 1,25(OH)2 vitamin D3, all of which are ligands that activate specific nuclear receptors [17]. Thus, it is clear that cholesterol plays a central role in the synthesis of many biologically active, small lipophilic molecules.
Section snippets
Oxysterols as negative regulatory molecules
Studies in the 1960s and 1970s demonstrated that addition of cholesterol to either cells in culture or animal diets inhibited the expression of HMG-CoA reductase, HMG-CoA synthase and the LDL receptor (reviewed in [3], [5]). Detailed studies by Kandutsch and colleagues demonstrated that various oxysterols were far more potent repressors than cholesterol [18]. Indeed, the slight repression by cholesterol could easily be explained by the production of oxysterols during prior storage of the sterol
SREBPs
Two genes, SREBP-1 and SREBP-2, encode three SREBP proteins, each with a molecular mass of approx. 125 kDa [3]. The SREBP-2 gene encodes a single protein that has approx. 50% identity with SREBP-1. As a result of alternative splicing and the use of alternative promoters, the SREBP-1 gene encodes two proteins, SREBP-1a and SREBP-1c, that differ only in the length of the amino terminal transactivation domain; as compared to SREBP-1c, SREBP-1a has 29 additional acidic-rich amino acids at the amino
SREBP target genes
Once the second cleavage of SREBPs has occurred, the mature proteins enter the nucleus, bind to SREs in the promoters of target genes (Table 1) and activate transcription. However, such activation requires additional transcription factors (see below). Activated genes identified to date include many that are involved in the control of cholesterol synthesis, LDL uptake, fatty acid synthesis and desaturation, triglyceride synthesis and glucose metabolism (Fig. 3 and Table 1). Indeed, the list of
Control of lipid and carbohydrate metabolism by SREBP, insulin and fasting
Although SREBP-2 mRNAs are expressed at a similar level in most tissues, the relative levels of SREBP-1a and SREBP-1c differ significantly. For example, in tissue culture cells, mRNAs encoding SREBP-1a>SREBP-1c. In contrast, the ratio of SREBP-1c:SREBP-1a can vary approx. 90-fold in animal tissues; the ratio is 9, 3, or 0.1 in liver, adipose tissue or spleen, respectively [51]. Assuming that there are similar changes in the protein levels, such differences are likely to be important, since many
Alternative control mechanisms: regulation of SREBP maturation by polyunsaturated fatty acids
A high carbohydrate/low fat diet induces the expression of several lipogenic and glycolytic enzymes, including ACC, FAS, SCD1, GPAT, ATP citrate lyase, pyruvate kinase, malic enzyme, S14 and glucose-6-phosphate dehydrogenase [64]. Recent studies, described above, indicate that such changes in gene expression likely result, at least in part, from the insulin-dependent activation of SREBP-1c. In contrast, addition of polyunsaturated fatty acids (PUFAs) to rodent diets results in a decline in the
Conclusion
The mechanisms involved in the synthesis and regulation of cholesterol have attracted many scientists over the last half century. The results of many of their studies have been spectacular, often unpredictable and have led to the development of drugs (e.g. statins) that have greatly influenced medical practice. The recent reports that demonstrate links between insulin, PUFAs and SREBPs and the control of cholesterol, fatty acid, triglyceride and glucose metabolism appear to open up new areas of
Acknowledgements
Space limitations prevented us from citing all relevant key references. To the authors of these omitted papers, we apologize. We thank Drs. Timothy Osborne and Matthew Kennedy for comments and Drs. J. Horton and I. Kurland for input into Fig. 2B. This work was supported by Grant HL30568 (to PAE) from the National Institutes of Health and a grant from the Laubisch Fund (to PAE). HRK was the recipient of a predoctoral training grant from the National Department of Education (# P200AB0113).
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