Why Some Fat Depots Waste but Others Expand in Patients Using Protease Inhibitors: Hypothesis and Supporting Data

W. J. FESSEL*. Kaiser Permanente Med. Ctr., San Francisco, CA

Background: The fat redistribution and hyperlipidemia that occur particularly when antiretroviral therapy (ART) includes a protease inhibitor (PI), are paradoxical in that acral and facial fat waste whereas central fat increases. There are two pools of fat, white and brown. In patients taking ART who experience fat redistribution, it is white fat that wastes in the extremities and face, and brown fat that expands in the upper back, neck, and abdomen. White fat has far fewer mitochondria than brown fat; thus nucleoside reverse transcriptase inhibitor (NRTI) toxicity to mitochondria disproportionately affects white fat. NRTIs cause wasting of white fat in the buttocks, limbs, and face but influence the levels of neither total nor HDL cholesterol. PIs may cause substantially elevated levels of total cholesterol and triglycerides but, generally, no concomitant rise in levels of HDL cholesterol.
Hypothesis: The paradox might be explained as follows. When white fat is damaged by NRTI, less of this pool is available, so that when fat needs to be stored the pool of brown fat is utilized and must expand. When patients take both PIs and NRTIs, low HDL means less LDL processed by the liver and, thus, more LDL to be stored. Brown fat expands by necessity since insufficient white fat is available for storage.
Supporting observations: The lowest levels of HDL and the highest ratios of total cholesterol : HDL should be observed in the patients with the greatest expansion of brown fat after taking PIs with NRTIs. This was so in 7 patients (group A) who had had surgical excision of extremely severe enlargement of the cervico-dorsal fat pad. Controls (group B) were all of the 29 patients taking 1 PI and 2 NRTIs, who had enrolled to date in a single research study. HDL was <35mg/dl in 100% of group A and in 34% of group B (P < .01); mean HDL was 30mg/dl in group A and 41mg/dl in group B. Total cholesterol : HDL ratio was >6.0 in 86% of group A and 45% of group B (P < .05). More baseline data for the 2 groups will be given.
Conclusion: The findings support the hypothesis; further studies are being made.

Key Words: brown fat, HDL cholesterol, lipodystrophy

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