HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus.
The mechanism by which human immunodeficiency virus (HIV) protease inhibitor therapy adversely induces lipodystrophy and hyperlipidemia has not been defined. This study explored the mechanism associated with the adverse effects of the prototype protease inhibitor ritonavir in mice. Ritonavir treatment increased plasma triglyceride and cholesterol levels through increased fatty acid and cholesterol biosynthesis in adipose and liver. Ritonavir treatment also resulted in hepatic steatosis and hepatomegaly. These abnormalities, which were especially pronounced after feeding a Western type high fat diet, were due to ritonavir-induced accumulation of the activated forms of sterol regulatory binding protein (SREBP)-1 and -2 in the nucleus of liver and adipose, resulting in elevated expression of lipid metabolism genes. Interestingly, protease inhibitor treatment did not alter SREBP mRNA levels in these tissues. Thus, the adverse lipid abnormalities associated with protease inhibitor therapy are caused by the constitutive induction of lipid biosynthesis in liver and adipose tissues due to the accumulation of activated SREBP in the nucleus.
Riddle
T M
TM
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0529, USA.
Kuhel
D G
DG
Woollett
L A
LA
Fichtenbaum
C J
CJ
Hui
D Y
DY
D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019438:Ritonavir / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D017320:HIV Protease Inhibitors; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D014157:Transcription Factors; D019438:Ritonavir