Sterol regulatory element-binding proteins and reactive oxygen species: potential role in highly-active antiretroviral therapy (HAART)-associated lipodystrophy.
OBJECTIVE
To summarize the existing pathophysiological concepts and to hypothesize new mechanisms involving sterol regulatory element-binding proteins (SREBP) and reactive oxygen species (ROS), in highly-active antiretroviral therapy (HAART)-associated lipodystrophy.


CONCLUSIONS
The widespread use of HAART has dramatically reduced AIDS-related deaths in the developed world. Unfortunately, long-term HAART has been associated with a unique and unexpected syndrome of lipodystrophy manifested by fat wasting in the subcutaneous adipose tissue of the face and extremities, and accumulation of fat in the viscera and neck, often accompanied by hyperlipidemia and insulin resistance. Despite intensive study of this syndrome over the past three years, the pathophysiologic mechanism(s) underlying HAART-associated lipodystrophy syndrome remains elusive. A continued attempt to elucidate pathophysiological mechanisms involved in HAART-associated lipodystrophy remains critically important to improving the treatment strategies for this epidemic condition. In this review, we suggest two new hypotheses that may explain the pathogenesis and pathophysiology of HAART-associated lipodystrophy that warrant further investigations. First, we hypothesize that upregulation and/or increase in the mature form of SREBP-1 caused by HAART may lead to perturbations in synergistic regulation of genes involved in maintenance of cholesterol homeostasis and synthesis of fatty acids, that may explain the accumulation of fat which is a hallmark of this syndrome. Second, we hypothesize that the generation of reactive oxygen species in adipocytes may be an early and critical event in HAART-associated toxicity leading to cell death, partially explaining the mechanism underlying lipoatrophy.
Nerurkar
P V
PV
Retrovirology Research Laboratory, Leahi Hospital, Honolulu, Hawaii 96816, USA. pneururka@pbrc.hawaii.edu
Shikuma
C M
CM
Nerurkar
V R
VR
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000273:Adipose Tissue / Q000378:metabolism; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008060:Lipodystrophy / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors