title: Effects of HIV protease inhibitor therapy on lipid metabolism.
abstract: Highly active antiretroviral therapy, which includes a combination of protease inhibitors, is highly successful in controlling human immunodeficiency virus (HIV) infection and reducing the morbidity and mortality of autoimmune deficiency syndrome (AIDS). However, the benefits of HIV protease inhibitors are compromised by numerous undesirable side effects. These include peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance. The mechanism associated with protease inhibitor-induced metabolic abnormalities is multifactorial. One major effect of the protease inhibitor is its suppression of the breakdown of the nuclear form of sterol regulatory element binding proteins (nSREBP) in the liver and adipose tissues. Hepatic accumulation of nSREBP results in increased fatty acid and cholesterol biosynthesis, whereas nSREBP accumulation in adipose tissue causes lipodystrophy, reduces leptin expression, and promotes insulin resistance. The HIV protease inhibitors also suppress proteasome-mediated breakdown of nascent apolipoprotein (apo) B, thus resulting in the overproduction and secretion of triglyceride-rich lipoproteins. Finally, protease inhibitor also suppresses the inhibition of the glucose transporter GLUT-4 activity in adipose and muscle. This latter effect also contributes directly to insulin resistance and diabetes. These adverse effects need to be alleviated for long-term use of protease inhibitor therapy in treatment of HIV infection.
authors.affiliation: Department of Pathology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA. huidy@email.uc.edu
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000139:chemically induced; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000502:physiology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D017320:HIV Protease Inhibitors; D008074:Lipoproteins; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors