HIV protease inhibitors block adipogenesis and increase lipolysis in vitro.
AIDS therapies employing HIV protease inhibitors (PIs) are associated with changes in fat metabolism. However, the cellular mechanisms affected by PIs are not clear. Thus, the affects of PIs on adipocyte differentiation were examined in vitro using C3H10T1/2 stem cells. In these cells the PIs, nelfinavir, saquinavir, and ritonavir, reduced triglyceride accumulation, lipogenesis, and expression of the adipose markers, aP2 and LPL. Histological analysis revealed nelfinavir, saquinavir and ritonavir treatment decreased oil red O-staining of cytoplasmic fat droplets. Inhibition occurred in the presence of the RXR agonist LGD1069, indicating the inhibitory effects were not due to an absence of RXR ligand. Moreover, these three PIs increased acute lipolysis in adipocytes. In contrast, two HIV PIs, amprenavir and indinavir, had little effect on lipolysis, lipogenesis, or expression of aP2 and LPL. Although, saquinavir, inhibited ligand-binding to PPARgamma with an IC(50) of 12.7+/-3.2 microM, none of the other PIs bound to the nuclear receptors RXRalpha or PPARgamma, (IC(50)s>20 microM), suggesting that inhibition of adipogenesis is not due to antagonism of ligand binding to RXRalpha or PPARgamma. Taken together, the results suggest that some, but not all, PIs block adipogenesis and stimulate fat catabolism in vitro and this may contribute to the effects of PIs on metabolism in the clinic.
Lenhard
J M
JM
Department of Metabolic Diseases, Glaxo Wellcome Inc., 5 Moore Drive, Research Triangle Park, NC 27709, USA. jml29514@glaxowellcome.com
Furfine
E S
ES
Jain
R G
RG
Ittoop
O
O
Orband-Miller
L A
LA
Blanchard
S G
SG
Paulik
M A
MA
Weiel
J E
JE
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D000077610:Bexarotene; D002219:Carbamates; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D050556:Fatty Acid-Binding Proteins; D005663:Furans; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D019469:Indinavir / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D019888:Nelfinavir / Q000494:pharmacology; D009363:Neoplasm Proteins; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D047488:Retinoid X Receptors; D019438:Ritonavir / Q000494:pharmacology; D000077154:Rosiglitazone; D019258:Saquinavir / Q000494:pharmacology; D013234:Stem Cells; D013449:Sulfonamides / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
D001391:Azo Compounds; D002219:Carbamates; D002352:Carrier Proteins; D004396:Coloring Agents; D050556:Fatty Acid-Binding Proteins; D005663:Furans; D017320:HIV Protease Inhibitors; D007328:Insulin; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone; C095108:amprenavir; D019469:Indinavir; D000077610:Bexarotene; D008071:Lipoprotein Lipase; C011049:oil red O; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir