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Increase in intracellular triglyceride synthesis induced by gemfibrozil
A Baldo1, A D Sniderman, K Cianflone
1McGill Unit for the Prevention of Cardiovascular Disease, Royal Victoria Hospital, Montreal, Quebec, Canada.
Metabolism: Clinical and Experimental
|February 1, 1994
Summary
Gemfibrozil significantly boosts triglyceride synthesis in human cells by affecting a key enzyme in the pathway. This study reveals a direct cellular mechanism for this lipid-lowering drug.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Gemfibrozil is a known hypotriglyceridemic agent.
- Its precise mechanism of action, particularly regarding lipoprotein lipase, is not fully understood.
Purpose of the Study:
- To investigate the hypothesis that gemfibrozil directly influences intracellular triglyceride synthesis in peripheral cells.
- To elucidate the cellular mechanism of gemfibrozil's hypotriglyceridemic effects.
Main Methods:
- Cultured human skin fibroblasts were treated with gemfibrozil.
- Triglyceride synthesis was measured using labeled glucose and fatty acids.
- Kinetic analysis (Lineweaver-Burk plots) was performed to determine changes in Km and Vmax.
- Experiments were also conducted on differentiated human preadipocytes and HepG2 cells.
Main Results:
- Gemfibrozil markedly stimulated triglyceride synthesis in a concentration-dependent manner.
- The stimulation was substrate-coordinated and sustained, with rapid onset.
- Kinetic analysis showed no change in Km but a significant increase in Vmax for both oleate and glucose.
- Similar effects were observed in preadipocytes and HepG2 cells.
Conclusions:
- Gemfibrozil directly enhances intracellular triglyceride synthesis in peripheral cells.
- The drug likely alters the active state of a rate-limiting enzyme in the triglyceride synthetic pathway.
- This study provides evidence for a direct cellular mechanism of gemfibrozil action beyond lipoprotein lipase effects.