Cholesterol Synthesis Linked to Diseases

In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig-1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low.

The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the "sterol regulatory element” of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL (low-density lipoprotein) receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, while HMG-CoA reductase leads to an increase of endogenous production of cholesterol.

In the current work, which was published in the June 2005 issue of Cell Metabolism, investigators at the Ludwig Institute for Cancer Research (Uppsala, Sweden) and Harvard Medical School (Boston, MA, USA) found that the Fbw7 protein degrades SREBP.

Fbw7 is a member of the F-box protein family, which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. Fbw7 belongs to the Fbws class; in addition to an F-box, this protein contains seven tandem WD40 repeats. It binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations of this gene are detected in ovarian and breast cancer cell lines. Insulin signaling inhibited Fbw7's ability to affect SREBP levels resulting in increased lipid and cholesterol synthesis.

Senior author Dr. Johan Ericsson, a researcher at the Ludwig Institute for Cancer Research, said, "We found that inhibiting Fbw7 resulted in increased SREBP levels and an enhanced uptake of LDL, so a drug that blocks the interaction between Fbw7 and SREBP proteins would probably enhance the removal of harmful LDL-cholesterol from the circulation. We can only speculate at this stage, but a two-pronged attack on LDL removal, combining a statin with a treatment that prevents Fbw7/SREBP interaction, would likely be of more benefit to some patients than statins alone.”





Related Links:
Ludwig Institute for Cancer Research
Harvard Medical School