October 25, 2001
This interesting study provides further evidence of the contribution of protease inhibitors (PIs) to the development of lipoatrophy. The impact of PIs described in these studies arises through effects on a key messenger within fat cells (adipocytes) known as Sterol Regulatory Element Binding Protein (SREBP). This messenger is involved in triggering stem cells, the basic cell from which our specialized cells arise, to change or differentiate into a pre-adipocyte -- the first big step on the road to growing into a mature fat cell. SREBP also acts on the chromosomes in the cell's nucleus to up-regulate the expression of the gene responsible for production of peroxisome proliferating activation factor (Ppar)-gamma. Ppar-g plays a number of cellular roles: it helps pre-adipocytes mature into adipocytes, and it helps the cell respond to insulin by reducing resistin, the insulin resistance regulator. Ppar-g also plays a role in immune cells. So, blocking SREBP is likely to have important effects on the production of new fat cells and on the sensitivity of those cells to insulin.
Dr. Capeau's studies, performed in vitro using stem cells and pre-adipocytes, demonstrated that PIs effect both the production of SREBP and its ability to up-regulate the gene responsible for Ppar-g production. Importantly, she also demonstrated that differences in impact exist between PIs. In general, indinavir was the worst offender for reducing SREBP's effects, nelfinavir a bit less so and amprenavir even less. Other PIs such as lopinavir, saquinavir and atazanavir were not tested.
The demonstrated effects were also important. All the PIs, and indinavir in particular, interfered with stem cell differentiation to pre-adipocytes and, subsequently, pre-adipocyte differentiation into mature adipocytes. The result was "abnormal" adipocytes. The abnormal cells were susceptible to apoptosis, the programmed cell death process which protects mammalian tissues from developing abnormalities. In undergoing apoptosis Dr. Capeau commented that the cells showed changes in their mitochondria and loss of mitochondrial DNA. Biopsy studies of fat from people with lipodystrophy (both areas of fat loss and fat accumulation) have previously reported increased fat cell apoptosis and changes in the mitochondria, including reductions in mitochondrial DNA. These studies had "blamed" the changes on nucleoside analog drugs such as AZT, as these drugs may be toxic to mitochondria in certain circumstances. However, this study provides evidence that these same changes can be induced, in vitro at least, just by PIs. Increased apoptosis and mitochondrial changes may be a characteristic of abnormal adipose tissue and not nucleoside analog toxicity.
Previous in vitro studies have indicated that PIs may trigger insulin resistance by blocking a receptor called GLUT4. This is the insulin-sensitive carrier on the surface of fat and muscle cells responsible for the uptake of glucose into fat cells. Mice with no GLUT4 have very little subcutaneous fat, suggesting that GLUT4 is important in laying down fat tissue. Indinavir, ritonavir, lopinavir, nelfinavir and amprenavir have all been reported to block GLUT4 in vitro, and indinavir is known to rapidly (within 2 weeks) induce insulin resistance in healthy volunteers. Dr. Capeau demonstrated that there is likely to be a second mechanism of insulin resistance brought about by PIs blocking the effects of SREBP -- hence production of Ppar-g. Her work suggested that this was through PIs preventing SREBP moving to the cell's nucleus to up-regulate the expression of the Ppar-g gene.
All this seems bad news for the use of the available PIs, although it may indicate that, if we have to use a PI, we should consider amprenavir before indinavir. As ritonavir has not been tested in these studies, we do not know how this drug -- established as a culprit in causing rises in cholesterol and triglycerides and which is usually given in small amounts with indinavir and amprenavir -- would alter the apparent differences in impact of these drugs on fat cells. It would also be helpful to know how newer PIs such as atazanavir and tipranavir, which have different chemical structures compared to the currently approved PIs, perform in these assays. NNRTIs and nucleoside analogs have also not been tested.
These studies suggest that at present we should be limiting our use of currently approved PIs, as they clearly have effects that may contribute to the syndrome. However, not everyone can avoid PIs. Can we do things to limit these potentially harmful effects. The answer from Dr. Capeau was a resounding "yes!"
She repeated these studies adding a thiazolinadione (or glitazone), rosiglitazone, to the mix. These types of drugs are used in mature onset (now called type II or insulin-resistant) diabetes where they sensitize cells to insulin by increasing Ppar-g. Two glitazones are currently approved, rosiglitazone and pioglitazone, with studies of both drugs getting underway in patients with HIV and lipoatrophy or insulin resistance. A previous member of this family, troglitazone was withdrawn from the market due to liver toxicity about 18 months ago, but before withdrawal had shown some benefit in patients with inherited forms of lipodystrophy, increasing the amount of fat under the skin in one study. The safety of current glitazones in HIV-positive patients has not been established, hence they cannot be currently recommended for use in routine clinical practice. However, in this test tube culture system, Dr. Capeau demonstrated that the effects of indinavir on fat cell maturation, insulin resistance and apoptosis were all rescued or prevented by the inclusion of rosiglitazone. While it takes leaps of faith to translate in vitro effects into real life, these data certainly underline the worth of investigating glitazones in patients with morphological changes.
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