Inhibition of adipocyte differentiation by HIV protease inhibitors.
Patients with AIDS who are receiving therapy with HIV protease inhibitors have been widely reported to be afflicted with a syndrome characterized by lipodystrophy (fat redistribution favoring the accumulation of abdominal and cervical adipose tissue), hyperlipidemia, and insulin resistance. HIV protease inhibitors have been suggested to have a direct role in modulating adipocyte differentiation. To address this hypothesis, several HIV protease inhibitors were studied for their ability to either augment or inhibit the differentiation of murine 3T3-L1 preadipocytes. Dose-responsive inhibition of adipogenesis by several protease inhibitors was noted as measured by reduced triglyceride accumulation and attenuated induction of three differentiation marker genes -- aP2, lipoprotein lipase, and Adipo Q. Potential mechanisms for altered adipocyte function, including direct binding to PPARgamma or inhibition of PPARgamma-mediated gene transcription were effectively excluded.
Zhang
B
B
Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA.
MacNaul
K
K
Szalkowski
D
D
Li
Z
Z
Berger
J
J
Moller
D E
DE
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology*; D052242:Adiponectin; D000818:Animals; D002219:Carbamates; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005663:Furans; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008071:Lipoprotein Lipase / Q000235:genetics; D051379:Mice; D018996:Myelin P2 Protein / Q000235:genetics; D019888:Nelfinavir / Q000494:pharmacology; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D052242:Adiponectin; D002219:Carbamates; D002352:Carrier Proteins; C107608:FABP7 protein, human; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005663:Furans; D006023:Glycoproteins; D017320:HIV Protease Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013449:Sulfonamides; D014157:Transcription Factors; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; C095108:amprenavir; D019469:Indinavir; D008071:Lipoprotein Lipase; D019888:Nelfinavir; D019438:Ritonavir