HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia.
Highly active anti-retroviral therapies, which incorporate HIV protease inhibitors, resolve many AIDS-defining illnesses. However, patients receiving protease inhibitors develop a marked lipodystrophy and hyperlipidemia. Using cultured human and rat hepatoma cells and primary hepatocytes from transgenic mice, we demonstrate that protease inhibitor treatment inhibits proteasomal degradation of nascent apolipoprotein B, the principal protein component of triglyceride and cholesterol-rich plasma lipoproteins. Unexpectedly, protease inhibitors also inhibited the secretion of apolipoprotein B. This was associated with inhibition of cholesteryl-ester synthesis and microsomal triglyceride transfer-protein activity. However, in the presence of oleic acid, which stimulates neutral-lipid biosynthesis, protease-inhibitor treatment increased secretion of apolipoprotein B-lipoproteins above controls. These findings suggest a molecular basis for protease-inhibitor-associated hyperlipidemia, a serious adverse effect of an otherwise efficacious treatment for HIV infection.
Liang
J S
JS
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Distler
O
O
Cooper
D A
DA
Jamil
H
H
Deckelbaum
R J
RJ
Ginsberg
H N
HN
Sturley
S L
SL
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001692:Biological Transport; D002788:Cholesterol Esters / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced / Q000209:etiology*; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009097:Multienzyme Complexes / Q000187:drug effects*; D019301:Oleic Acid / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001055:Apolipoproteins B; D002788:Cholesterol Esters; D017320:HIV Protease Inhibitors; D008074:Lipoproteins; D009097:Multienzyme Complexes; D018894:Reverse Transcriptase Inhibitors; D014280:Triglycerides; D019301:Oleic Acid; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex