CPT-1, carnitine palmitoyltransferase-1 (see Fig. 4.3); FABP, fatty acid binding protein. *The apolipoproteins and their functions are described in Chapter 9.
fThe isoforms PPARyl and PPAR-y2 are produced from the same gene by use of different promoters. Based on Gurr etal. (2002).
Not all fatty acids are equally active in activating the PPARs. Polyunsaturated fatty acids are more potent than saturated fatty acids, and amongst the former, the n-3 series are more potent than the n-6 series. This probably relates also to the marked effect of n-3 polyunsaturated fatty acids in lowering plasma triacylglycerol concentrations, discussed in a later chapter (see Box 9.5). Fatty acids also interact with the sterol regulatory element binding protein system described in the next section.
The PPAR system has aroused intense interest because of the potential for pharmacological manipulation. Again, in the 1960s it was observed by chance that a new pesticide was causing illness amongst farmers, and on investigation they were found to have low serum cholesterol concentrations. This led to the discovery of clofibrate, the first drug reliably able to lower serum cholesterol levels. Clofibrate is a peroxisome proliferator: it is a ligand for PPARa. Clofibrate turned out to have some undesirable side effects, but a group of drugs was developed from it: the fibrates or fibric acid derivatives. These drugs play an important role in lowering elevated serum lipid concentrations. In fact they are more potent in lowering elevated triacylglycerol concentrations than elevated cholesterol, as we might predict knowing the effects of PPARa activation. They also have beneficial effects on some proteins involved in lipid metabolism; this will be discussed in Chapter 9 (Section 9.4.3).
During the search for new agents acting like the fibrates, a group of drugs was discovered that has the effect of lowering blood glucose concentrations, apparently by improving the sensitivity of tissues to the actions of insulin. These drugs are now called the thiazolidinediones or 'glitazones' and they are already in use for the treatment of diabetes. After their discovery, it was found that they are ligands for PPARy. One possibility is that they act by increasing the ability of adipose tissue to store excess fatty acids as triacylglycerol: thus, circulating fatty acid concentrations are reduced, and tissues such as skeletal muscle are able to utilise more glucose because of reduced substrate competition.
One of the first systems to be fully understood by which nutrients or cellular constituents regulate gene expression was that for cholesterol. This will be discussed again in more detail in Chapter 9, but is covered here because the system is now recognised to have more general importance. All cells with nuclei can synthesise cholesterol from cytosolic acetyl-CoA, and can also acquire it from the plasma through a specific cell-surface receptor (the LDL receptor, described in detail in Chapter 9). Cells regulate their own cholesterol content by adjusting expression of the key enzymes of cholesterol synthesis, particularly the first committed step in cholesterol synthesis from cytosolic acetyl-CoA, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase; described later, Box 4.3). Expression of the LDL receptor is also regulated in parallel. These genes were considered to have a regulatory element responsive to sterols (i.e. to cholesterol or related compounds), i.e. a sterol regulatory element. The sterols
Increased expression Increased expression of enzymes of LDL-receptor of cholesterol synthesis
Was this article helpful?
All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.