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Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

Recent data suggest that sterol regulatory-binding protein (SREBP)-1c plays a key role in the transcriptional regulation of different lipogenic genes mediating lipid synthesis as a key regulator of fuel metabolism. SREBP-1c regulates its downstream genes by changing its own mRNA level, which led us to sequence and analyze the promoter region of the mouse SREBP-1c gene. A cluster of putative binding sites of several transcription factors composed of an NF-Y site, an E-box, a sterolregulatory element 3, and an Sp1 site were located at ؊90 base pairs of the SREBP-1c promoter. Luciferase reporter gene assays indicated that this SRE complex is essential to the basal promoter activity and confers responsiveness to activation by nuclear SREBPs. Deletion and mutation analyses suggest that the NF-Y site and SRE3 in the SRE complex are responsible for SREBP activation, although the other sites were also involved in the basal activity. Gel mobility shift assays demonstrate that SREBP-1 binds to the SRE3. Taken together, these findings implicate a positive loop production of SREBP-1c through the SRE complex, possibly leading to the overshoot in induction of SREBP-1c and its downstream genes seen in the livers of refed mice. Furthermore, reporter assays using larger upstream fragments indicated another region that was inducible by addition of sterols. The presence of the SRE complex and a sterolinducible region in the same promoter suggests a novel regulatory link between cholesterol and fatty acid synthesis.Sterol regulatory element-binding proteins (SREBPs) 1 are transcription factors that belong to the basic helix-loop-helix leucine zipper family (1, 2). In contrast to other members of this family, SREBPs are synthesized as precursor proteins that remain bound to the endoplasmic reticulum and the nuclear envelope in the presence of sufficient sterol concentrations. Upon sterol deprivation, the precursor protein undergoes a sequential two-step cleavage process to release the NH 2 -terminal portion (3). This mature SREBP then enters the nucleus and activates the transcription of genes involved in cholesterol and fatty acid synthesis by binding to sterol regulatory elements (SREs) or to palindromic sequences called E-boxes within their promoter regions (4, 5). Currently, there are three forms of SREBP that have been characterized; SREBP-1a and -1c are derived from a single gene through the use of alternate promoters and SREBP-2 from a different gene. SREBP-1a is the more common isoform and is a stronger activator of transcription with a wider range of target genes than SREBP-1c because of a longer transactivation domain (6). Transgenic mouse studies have shown that SREBP-1c plays a more active role in regulating the transcription of genes involved in fatty acid synthesis than those involved in cholesterol synthesis, whereas SREBP-1a activates both (6, 7). SREBP-2 is known to be actively involved in the transcription of cholesterogenic enzymes (8). It has been shown that all cultured cells analyzed to date exclusively expre...

We show in this manuscript that expression of the mRNA for sterol regulatory element-binding protein-2 (SREBP-2) is regulated by the cellular sterol level in cultured HeLa cells. We have cloned the 5 -flanking region of the gene encoding human SREBP-2. Characterization of this region shows the minimum 50-base pair segment, which contains a 10-base pair sterol regulatory element 1 (SRE-1) identical to the one in the human LDL receptor promoter, confers sterol responsiveness when fused to the luciferase reporter gene. Enforced expression of the truncated SREBP-2 protein (amino acid residues 1-481) also shows that this upstream segment contains the information required for transcriptional activation. The luciferase assays using mutant versions of the reporter genes reveal that the sterol-dependent transcriptional regulation is mediated by two nearby motifs, the SRE-1 and the NF-Y binding site (the inverted CCAAT box, ATTGGC); the latter is reported to play a critical role in sterol-dependent regulation of 3-hydroxy-3-methylglutaryl-coenzyme A synthase and farnesyl diphosphate synthase genes (Jackson, S. M., Ericsson, J., Osborne, T. F., and Edwards, P. A. (1995) J. Biol. Chem. 270, 21445-21448). Gel mobility shift assays demonstrate that the transcription factor NF-Y truly binds to the ATTGGC sequence. These findings suggest that the activity of SREBP-2 is controlled not only post-translationally by proteolytic activation of the precursor protein but also transcriptionally by itself together with NF-Y.Two structurally related sterol regulatory element-binding proteins, designated SREBP-1 and SREBP-2, 1 are implicated to be central regulators in cholesterol and fatty acid metabolisms; the binding of SREBPs to a 10-bp sterol regulatory element (SRE-1) elicits the transcriptional activation of downstream genes such as HMG CoA synthase and the LDL receptor (1, 2). Recent studies have also demonstrated that SREBPs are involved in transcriptional control of the genes for farnesyl diphosphate synthase (3), squalene synthase (4), fatty acid synthase, and acetyl CoA carboxylase (5-7).SREBPs are synthesized as 125-kDa membrane-bound precursors that are localized on the nuclear envelope and the endoplasmic reticulum (8, 9). In sterol-depleted cells the precursors are proteolytically cleaved to generate soluble NH 2 -terminal fragments (designated as the mature form with ϳ480 amino acids) containing an acidic transactivation domain and a basic helix-loop-helix-leucine zipper region that mediates protein dimerization and DNA binding. The mature form translocates to the nucleus and activates transcription. When sterols accumulate within cells, the precursors are no longer proteolysed but remain on the membranes, resulting in the decline in transcription of sterol-regulated genes.In addition to the proteolytic activation of precursor proteins, here we report that mRNA expression for SREBP-2 is regulated by the cellular cholesterol level. The 5Ј-flanking region of the human SREBP-2 gene has been found to contain the SRE-1 and the ...

Recent studies on the in vivo roles of the sterol regulatory element binding protein (SREBP) family indicate that SREBP-2 is more specific to cholesterogenic gene expression whereas SREBP-1 targets lipogenic genes. To define the molecular mechanism involved in this differential regulation, luciferase-reporter gene assays were performed in HepG2 cells to compare the transactivities of nuclear SREBP-1a, -1c, and -2 on a battery of SREBP-target promoters containing sterol regulatory element (SRE), SRE-like, or E-box sequences. The results show first that cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c. Second, an E-box containing reporter gene is much less efficiently activated by SREBP-1a and -1c, and SREBP-2 was inactive in spite of its ability to bind to the E-box. Third, promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2. Finally, substitution of the unique tyrosine residue within the basic helix-loop-helix (bHLH) portion of nuclear SREBPs with arginine, the conserved residue found in all other bHLH proteins, abolishes the transactivity of all SREBPs for SRE, and conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes.These data demonstrate the different specificity and affinity of nuclear SREBP-1 and -2 for different target DNAs, explaining a part of the mechanism behind the differential in vivo regulation of cholesterogenic and lipogenic enzymes by SREBP-1 and -2, respectively.