Cause of lipid increases becomes clearer

The development of protease inhibitors which do not cause metabolic complications may have come a step closer thanks to important discoveries made by a joint American and Australian research team.

In a study published in the December issue of Nature Medicine, scientists at Columbia University, New York conducted a laboratory test to analyse how protease inhibitors damage the ability of the liver cells to assemble lipoprotein particles. Lipoprotein particles, also known as VLDLs, LDLs and HDLs, are large complexes of molecules that transport cholesterol and other fats through the blood. The liver also manufactures apolipoproteins, which sit on the surface of the lipoprotein and direct the particles on where to deliver fat within the body. Although both fat and cholesterol are essential for a healthy body, too much can clog the arteries and cause cardiovascular disease.

The Columbia team found that protease inhibitors block a mechanism for the break down of a substance in liver cells called apolipoprotein B. Significantly, apolipoprotein B is involved in the early stages of the formation of LDL cholesterol, elevated levels of which are known to be a major cause of heart disease. Researchers found that liver cells in people treated with the protease inhibitors ritonavir and saquinavir had elevated levels of apolipoprotein B particles. The investigators suggest that the accumulated apolipoproteins are released into the blood stream as VLDL and LDL cholesterol after a person on protease inhibitors eats a meal rich in fatty acids.

The site at which protease inhibitors inhibit the break down of apolipoprotein is called the proteasome, and is one of numerous points within lipid and glucose metabolism now shown to be directly inhibited by protease inhibitors in laboratory studies.

Protease inhibitors have also been shown to inhibit the activity of GLUT4, a transporter of glucose located on the surface of cells which takes up glucose from the bloodstream for use in cells. Inhibition of GLUT4 has been directly related to insulin resistance in HIV-negative humans treated with indinavir (Noor). Several studies have also shown that protease inhibitors directly affect the development of adipocytes (fat cells) in the test tube, acting on chemicals known as transcription factors that govern the process by which cells receive their instructions on how to become fully functioning fat cells. Different PIs seem to have different effects on this process, with indinavir seemingly the most toxic and amprenavir the least (Capeau).

This evidence, together with previous data, adds to the accumulating picture of HIV-associated lipodystrophy as a multi-factorial syndrome in which multiple mechanisms act together to produce widely varying patterns of fat redistribution and metabolic disturbance according to characteristics of the person taking HIV drugs and the specific drugs they are taking.

Using liver assay tests, it is hoped that a future generation of protease inhibitors can be developed which do not cause an accumulation of apolipoprotein B. It is also hoped that liver assay tests could also identify which of the currently licensed protease inhibitors are most likely to cause the disturbances which can lead to the build up of LDL cholesterol.