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HIV protease inhibitors stimulate hepatic triglyceride synthesis
J M Lenhard1, D K Croom, J E Weiel
1Department of Metabolic Diseases, GlaxoWellcome Inc, Research Triangle Park, NC 27709, USA. jml29514@glaxowellcome.com
Arteriosclerosis, Thrombosis, and Vascular Biology
|December 16, 2000
Summary
HIV protease inhibitors (PIs) can cause hyperlipidemia by increasing triglyceride synthesis in liver cells and mice. Retinoids and meal timing may influence these lipid metabolism effects.
Area of Science:
- Biochemistry
- Pharmacology
- Hepatology
Background:
- Hyperlipidemia is a potential complication of HIV protease inhibitor (PI) therapy for AIDS.
- Understanding the mechanisms behind PI-induced hyperlipidemia is crucial for patient management.
Purpose of the Study:
- To investigate the effects of various PIs on lipid metabolism in vitro and in vivo.
- To elucidate the role of hepatic triglyceride synthesis in PI-associated hyperlipidemia.
Main Methods:
- Experiments were conducted using HepG2 liver cells and AKR/J mice.
- Lipid synthesis, mRNA expression, and serum lipid profiles were analyzed.
- In vivo studies involved fed and fasted mice, with and without Triton WR-1339 administration.
Main Results:
- Specific PIs (ABT-378, nelfinavir, ritonavir, saquinavir) stimulated triglyceride synthesis in HepG2 cells; ritonavir also increased cholesterol synthesis.
- Nelfinavir elevated mRNA expression of key enzymes involved in fatty acid synthesis.
- In mice, PIs increased serum triglycerides and fatty acids, with varying effects on glucose and cholesterol depending on feeding status.
Conclusions:
- PI-associated hyperlipidemia is likely caused by increased hepatic triglyceride synthesis.
- The effects of PIs on lipid metabolism may be modulated by retinoids and meal timing/restriction.