2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13-15 September 2000, Toronto, Canada

SELECT HIV PROTEASE INHIBITORS STIMULATE HEPATIC TRIGLYCERIDE SYNTHESIS AND PANCREATIC LIPASE ACTIVITY

Antiviral Therapy 2000; 5(Suppl. 5):29 (abstract no. P9)

J Lenhard, D Croom, J Weiel and D Winegar
Department of Metabolic Diseases, Glaxo Wellcome, Research Triangle Park, N.C., USA

BACKGROUND: Hyperlipidaemia may complicate the use of HIV protease inhibitors (PIs) in AIDS therapy.

OBJECTIVE: To determine if hepatic triglyceride synthesis and pancreatic lipase contribute to PI-associated hyperlipidemia.

DESIGN: The effect of PI was examined on lipid synthesis in human HepG2 liver cells and triglyceride production and pancreatic lipase in AKR/J mice.

RESULTS: In HepG2 cells, 10 µM of the PI ABT-378, nelfinavir, ritonavir and saquinavir stimulated triglyceride synthesis, ritonavir increased cholesterol synthesis, and amprenavir and indinavir had no effect. Moreover, nelfinavir increased mRNA expression of diacylglycerol acyltransferase and fatty acid synthase (FAS). Retinoid X receptor agonists, but not antagonists, further increased PI-stimulated triglyceride synthesis and mRNA expression of FAS in vitro. In fed mice, nelfinavir or ritonavir did not affect glucose and cholesterol, whereas triglyceride and fatty acids increased 57-108%. In fasted mice, ritonavir increased glucose (29%), cholesterol (40%) and triglyceride (99%), whereas nelfinavir had no effect, suggesting PI have different effects in fed and fasted mice. Consistent with the in vitro results, 30 mg/kg nelfinavir and ritonavir (twice daily for 2 weeks) increased triglyceride levels two- to threefold in fasted mice injected with Triton WR-1339, an inhibitor of triglyceride clearance. Furthermore, treatment of AKR/J mice with nelfinavir, ritonavir and indinavir, but not amprenavir or saquinavir, increased pancreatic lipase activity, an enzyme that hydrolyses intestinal diglycerides and contributes to dietary fat absorption.

CONCLUSIONS: We propose PI-associated hyperlipidaemia is due to increased hepatic triglyceride synthesis and suggest that meal restriction or dietary retinoids influence the effects of PIs on lipid metabolism. Additionally, select PIs may cause hyperlipidaemia by increasing pancreatic lipase activity and absorption of dietary fat.

000913
P9

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