How ART might cause lipodystrophy

Antiretrovirals have been shown to affect several key stages regulating the development of fat cells.

Fat cells (adipocytes) develop from precursors called adipoblasts, which differentiate, or take on the full characteristics of adipocytes, by exposure to a sequence of agents called transcription factors. If one agent in the cascade is withheld, this can affect the activity of the rest of the chain, leading to faulty fat cells.

In the case of HIV-associated lipodystrophy, defects have been noted in the nuclei of fat cells which indicate that a gene called lamin A/C is being impaired. A similar defect is responsible for the inherited form of lipodystrophy called Dunnigan's lipodystrophy. Researchers believe that in the case of HIV lipodystrophy, the defect could be caused by the inhibition by HIV protease inhibitors of cellular proteases that are involved in maturation of a transcription factor involved in adipocyte differentiation called SREBP-1, which must be incorporated into the maturing adipocyte nucleus by the lamina. Any defect in lamin A/C would affect this process of incorporation.

Nucleoside analogues (NRTIs) have also been shown to affect adipocytes by increasing apoptosis (programmed cell death), especially when combined with protease inhibitors. However, they have also been shown to reduce the impact of protease inhibitors on adipocyte differentiation (although not to suppress this effect entirely). A French group found that d4T and AZT decreased cell lipid content and slightly increased apoptosis.¹

Another avenue by which adipocyte activity can be altered is through induction of TNF-alpha and interleukin-6 production by protease inhibitors and by NRTIs. TNF-alpha reduces adipocyte differentiation, most specifically by affecting SREBP-1 activity. One study showed that indinavir, AZT and d4T each increased TNF-alpha gene expression, implying increased production.

What remains unclear is the extent to which elevated TNF-alpha production is a direct effect of individual agents, compared to an effect of dysregulated immune reconstitution. Whilst in vitro evidence has pointed to the former, at least one in vivo study has shown that the dysregulation of TNF-alpha production is not restricted to adipocytes during immune reconstitution, but is a more generalised phenomenon caused by the suppression of lymphocyte apoptosis by protease inhibitors. ^{2 3} This dysregulation was strongly correlated with the presence of lipodystrophy and metabolic changes such as elevated triglycerides.

Drug-related defects in adipocyte functioning would provide an adequate explanation for many of the phenomena associated with lipodystrophy. Defects in adipocyte differentiation and increased apoptosis would tend to appear first in peripheral fat, leading to loss of fat cells. Increased insulin resistance would lead to increased release of free fatty acids from adipocytes (lipolysis), leading in turn to higher triglyceride levels and further insulin resistance. Increased efflux of free fatty acids from adipocytes has also been associated with d4T treatment and with nelfinavir. ⁴

Visceral fat accumulation in the abdomen may be attributable to disruption of growth hormone and cortisol production. Whilst growth hormone limits central fat accumulation, cortisol encourages it. If TNF-alpha production is increased in adipose tissue, it will suppress activate cortisol synthesis if human growth hormone levels are deficient. Visceral fat accumulation would be aggravated by any increase in triglyceride levels or reductions in insulin sensitivity.

However, metabolic regulation of adipose tissue is extremely complex, and as the lack of a cure for obesity shows, difficult to unravel.

For example, studies in transgenic mice which lack subcutaneous fat show that these mice have a similar pattern of metabolic abnormalities to those seen in HAART-associated lipoatrophy (elevated triglycerides and diabetes type II). When a large quantity of subcutaneous fat from a normal mouse was transplanted into the fat-less mouse, the metabolic abnormalities disappeared. This study suggests that subcutaneous adipose tissue is a metabolic regulator, and that its disappearance may be partially responsible for the severe metabolic disturbances seen in people with lipoatrophy. ⁵

A UK Open University group has theorised that the development of lipodystrophy is influenced by the interaction between lymph nodes and adipose tissue. Animal experiments show that chronic stimulation of lymph nodes from the central fat depots led to proliferation of new lymph nodes, whilst peripheral fat stores were drained (peripheral fat does not contain lymph nodes).⁶