Regulation of fatty acid and cholesterol synthesis: co-operation or competition?

Fatty acids and sterols originally evolved symbiotically as structural components of cell membranes. In some respects, control of their biosynthetic pathways reflects their mutual interdependence in defining changes in the physicochemical properties of the membranes in response to the changing internal and external cellular environments. In some tissues of higher animals, however, cholesterol and fatty acids have multifunctional roles. In particular, the liver synthesizes these lipids for export as multimolecular complexes in the form of micellar bile components and lipoproteins. Intrahepatic fatty acid and cholesterol synthesis is dependent upon the balance between hepatic output of these complexes and dietary input of fat and cholesterol. Thus physiological control of these synthetic processes is often co-ordinated at both the transcriptional and post-translational levels. On the other hand, changes in flux through major metabolic pathways, particularly during physiological transitions and as a result of genetic manipulation, affects substrate availability for these pathways. Under these circumstances, regulation reflects a compensatory response to ensure that flux through the lipid pathways remains unchanged. These regulatory changes can best be interpreted in terms of a Metabolic Control Analysis approach. In summary, flux through the fatty acid and cholesterol pathways reflects (a) cellular demand for these lipids, (b) a variable availability of substrates, (c) a combination of (a) and (b).