Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus protease inhibitors induce hyperlipidemia in many patients treated with these drugs. We examined the effects of indinavir on cholesterol and bile acid homeostatic mechanisms in a primary rat hepatocyte (PRH) culture model. In PRH, indinavir up-regulated (2.5-fold) 3-hydroxy-3-methylglutaryl-Coenzyme A reductase mRNA levels 24hr after drug addition. In these same experiments, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels, the rate-limiting enzyme in bile acid biosynthesis, was decreased up to 10-fold. Fatty acid synthase mRNA levels were up-regulated more than 3-fold under these conditions. Indinavir did not alter CYP7A1 transcriptional activity, but decreased CYP7A1 mRNA half-life in PRH from 1.5hr to less than 0.5hr. Sterol regulatory element-binding protein-1 (SREBP-1) mature form was increased approximately 6-fold by this drug. Indinavir-induced mRNA changes and SREBP-1 mature protein levels were significantly abated by the addition of cholesterol, solubilized in beta-cyclodextrin, to culture medium. Indinavir markedly decreased endogenous cholesterol esterification and increased cholesterol in intracellular membranes in primary hepatocytes. Indinavir gavaged into intact mice also markedly increased SREBP-1 and SREBP-2 (mature forms) in hepatic nuclei. CYP7A1 mRNA was also decreased approximately 52% in indinavir-treated animals. We propose that indinavir disrupts cellular cholesterol homeostasis by increasing SREBP's and decreasing CYP7A1 mRNA.
 ...
PMID:Indinavir alters sterol and fatty acid homeostatic mechanisms in primary rat hepatocytes by increasing levels of activated sterol regulatory element-binding proteins and decreasing cholesterol 7alpha-hydroxylase mRNA levels. 1469 38

Treatment of human immunodeficiency virus (HIV)-infected patients with HIV protease inhibitors (PIs) has been associated with serious lipid disturbances. However, the incidence and degree of impaired lipid metabolism observed in the clinic vary considerably between individual HIV PIs. Our previous studies demonstrated that HIV PIs differ in their ability to increase the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs), activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. In the present study, we examined the effects of three HIV PIs, including amprenavir, atazanavir, and ritonavir, on the UPR activation and the expression of key genes involved in lipid metabolism in primary rodent hepatocytes. Both atazanavir and ritonavir activated the UPR, induced apoptosis, and increased nuclear SREBP levels, but amprenavir had no significant effect at the same concentrations. In rat primary hepatocytes, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels were significantly decreased by atazanavir (38%) and ritonavir (56%) but increased by amprenavir (90%); 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase mRNA levels were increased by amprenavir (23%) but not by ritonavir and atazanavir; low-density lipoprotein receptor mRNA was increased by atazanavir (20%) but not by amprenavir and ritonavir. Similar results were obtained in mouse primary hepatocytes. Atazanavir and ritonavir also decreased CYP7A1 protein levels and bile acid biosynthesis, while amprenavir had no significant effect. The current results may help provide a better understanding of the cellular mechanisms of HIV PI-induced dyslipidemia and also provide useful information to help predict clinical adverse effects in the development of new HIV PIs.
 ...
PMID:HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes. 1686 Dec 19