Increase in intracellular triglyceride synthesis induced by gemfibrozil.
Gemfibrozil is an effective hypotriglyceridemic agent. Its mechanism of action has not been determined with certainty, but it is generally thought to act by virtue of an effect on lipoprotein lipase. However, this study was designed to test the hypothesis that gemfibrozil directly affects intracellular triglyceride synthesis in peripheral cells, and indeed, when added to the medium, gemfibrozil markedly stimulated triglyceride synthesis in cultured human skin fibroblasts. The effect was concentration-dependent, with a maximum effect at a gemfibrozil concentration of 40 micrograms/mL. A marked increase in triglyceride synthesis was observed when either labeled glucose or labeled fatty acid were added to the medium, indicating that the stimulation was substrate-coordinated. The effect was sustained for hours, with an onset of action within minutes. Lineweaver-Burk plots were constructed, and these revealed no apparent change in Km for either oleate or glucose (8.18 +/- 2.97 v 6.40 +/- 2.10 mumol/L for oleate and 0.113 +/- 0.004 v 0.107 +/- 0.051 mmol/L for glucose, control v gemfibrozil, P = NS). By contrast, there was a significant increase in the maximum triglyceride synthetic rate (Vmax) for both oleate and glucose (14.57 +/- 0.01 v 32.66 +/- 1.85 nmol/mg/4 h for oleate and 67.72 +/- 1.22 v 156.77 +/- 17.61 nmol/mg/4 h for glucose, control v gemfibrozil, P < .025). Given the rapid onset in action, these data suggest that gemfibrozil altered the active state of a limiting step in the triglyceride synthetic pathway. The effect of gemfibrozil on triglyceride synthesis was also determined on differentiated human preadipocytes and HepG2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Baldo
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McGill Unit for the Prevention of Cardiovascular Disease, Royal Victoria Hospital, Montreal, Quebec, Canada.
Sniderman
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AD
Cianflone
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K
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D005347:Fibroblasts / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis*
D014280:Triglycerides; D015248:Gemfibrozil