Delicious, no doubt, but some foods we like are sadly linked to the production of low-density lipoprotein (LDL) cholesterol, a major risk factor for the development of athersclerosis, and consequent heart disease and stroke. The statin class of drugs have had a tremendous impact on lowering circulating levels of LDL cholesterol, but statins don't work for everybody, often failing to produce a sufficient reduction, and occasionally giving rise to serious side effects. So, the discovery of a new class of hypolipidaemic drugs, known as 'SCAP ligands', as reported in December's Nature Medicine, is very welcome news.

Whereas statins work by directly inhibiting the rate-limiting enzyme in the cholesterol synthesis pathway, the newly reported compounds seem to act indirectly, by increasing the level of expression of the cell-surface LDL receptor (LDLR), which removes cholesterol from the circulation. Expression of LDLRs is under the control of transcriptional activators known as sterol-response-element-binding proteins (SREBPs). To drive the formation of new LDLRs, the SREBPs need to travel from the cell's endoplasmic reticulum into the nucleus, while also undergoing a two-stage cleavage process. They are chaperoned on their journey by another protein called SCAP, the SREBP-cleavage-activating protein. The authors propose that their new compounds act directly to activate SCAP, driving the cleavage of SREBPs and the consequent formation of new LDLRs, thus lowering the level of LDL cholesterol.

To test the hypolipidaemic potential of these SCAP ligands, hamsters fed on a high-fat diet were treated with one of the compounds for 3 days. Circulating LDL levels were found to be reduced by about two-thirds, whereas levels of high-density lipoprotein (HDL) cholesterol, often know as 'good cholesterol', were unaffected. Supportive of the authors' theory that this lowering was due to increased expression of LDLR, the livers from these same animals showed a threefold rise in the level of transcripts encoding the receptor.

Despite occasional high-profile problems with statins, such as the withdrawal of Bayer's cerivastatin (Baycol) last summer following the deaths of 31 patients in the United States, the success and wide usage of statin-based therapy indicates that the main need is now for therapies that augment, rather than replace, statins as the first line of defence against atherosclerosis. SCAP ligands now take their place among several potential new therapies for lowering cholesterol, some of which are already in clinical development, but which will all eventually need to show efficacy in patients already receiving statins.