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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2004 November 1;10(21):3081-3087

Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins 

Lutz W. Weber, Meinrad Boll, Andreas Stampfl

Lutz W. Weber, 554 Mariner Point Drive, Clinton, TN 37716, USA
Meinrad Boll, Andreas Stampfl, Institute for Toxicology, GSF - National Research Center for Environment and Health, Munich, D-85758 Neuherberg, Germany
Correspondence to: Lutz W. Weber, Institute of Toxicology, GSF - National Research Center for Environment and Health, Munich, D-85758 Neuherberg, Germany.
Telephone: +49-89-3187-2625    Fax: +49-89-3187-3449
Received: 2003-10-15    Accepted: 2004-04-13

The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins are members of the basic helix-loop-helix-leucine zipper (bHLH-Zip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP).The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.

Weber LW, Boll M, Stampfl A. Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins. World J Gastroenterol  2004; 10(21): 3081-3087

The view of cholesterol as a nasty substance which clogs arteries and causes heart disease is wide-spread, but it does not do the molecule justice. Not only is it a vital component of cell membranes without which the cell cannot function, but it is also the precursor to all steroid hormones, bile acids, and oxysterols, which by themselves are important regulatory molecules in many metabolic pathways.
     Cholesterol and fatty acids as building blocks of cell membranes are synthesized via regulated pathways. All cells must control  these pathways in order to maintain levels within physiological boundaries. Excessive amounts of cholesterol in cells can destroy membrane function, precipitate as crystals which will kill the cell or result in atherosclerotic damage if spread to blood[1]. However, the original view of random distribution of cholesterol and lipids in the cell membrane no longer holds: not only differs the lipid composition of the outer leaflet of the plasma membrane from the inner one, but the distribution of lipids and cholesterol in the outer leaflet is organized into domains, with so-called rafts[2] and caveolae[3] being rich in cholesterol and sphingomyelin. These structures play intricate roles in cholesterol trafficking to maintain cellular homeostasis, and they are also components of the cellular signalling system.  The membranes of endoplasmic reticulum (ER) and Golgi, on the other hand, contain comparatively little cholesterol, a factor important in its own homeostasis, and one objective of this overview.
      The understanding of cholesterol regulation has come a long way from the initial recognition of cholesterol feedback inhibition of its rate-limiting synthetic enzyme, 3-hydroxy-3- methylglutaryl coenzyme A (HMGCoA) reductase, through the role of lipoproteins in maintaining plasma cholesterol levels, to the recent discoveries of regulation of cholesterol synthesis via sterol-sensitive response elements (SREs), and degradation via liver X receptor (LXR) - or bile acid receptor (BAR) -regulated pathways.
      Lipid homeostasis via SREs in animal cells is achieved by a family of transcription factors called SRE-binding proteins (SREBPs). SREBPs activate directly the expression of some 30-plus genes participating in the metabolism mostly of lipids, but also glucose. Activation of these originally membrane-bound transcription factors involves a proteolytic cascade through which the SREBP molecule is released from the membrane and obtains its mature form as a transcription factor. The active SREBP enters the nucleus and binds to those special DNA sequences, the SREs, in the promoter regions of many different genes.
      In the health arena, SREBPs stand at a crucial point: they regulate expression of the LDL receptor, the molecule which enables the hepatocytes to remove cholesterol contained in LDL particles from the bloodstream. High (dietary) cholesterol prevents maturation of SREBPs and not only cuts off cholesterol synthesis, but also LDL receptor synthesis, resulting in high blood cholesterol and the imminent danger of atherosclerotic plaque formation. At this point in time the so-called statins, drugs which block HMGCoA reductase, another target of SREBP-mediated gene expression, are the most effective way to interrupt this vicious circle[4].
     This brief overview is concerned with the