Selective modification of rat hepatic microsomal fatty acid chain elongation and desaturation by fibrates: relationship with peroxisome proliferation.
1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-, palmitoleoyl- and gamma-linolenoyl-CoA elongase, delta-9, delta-6 and delta-5 desaturase activities, and microsomal electron transport chains, as well as the correlation with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2. As reported in our previous work, the three drugs behave as peroxisomal proliferators (the order of potency was BFB > CFB > or = GFB) and induced a clear reduction in both plasma cholesterol and triglyceride levels. 3. Palmitoyl-CoA elongation activity was increased by the three drugs (BFB = GFB > CFB), whereas palmitoleoyl-CoA elongation activity was only enhanced by GFB. Elongation activity was not modified by fibrates when gamma-linolenoyl-CoA was used as substrate. These results are in accordance with the existence of three different elongation systems for saturated, mono- and polyunsaturated fatty acids. 4. delta-9, delta-6 and delta-5 desaturase activities were increased by the three fibrates, with an order of potency BFB > CFB = GFB for delta-9 and delta-5, and GFB > BFB = CFB for delta-6. 5. Of the enzyme activities integrated in the microsomal electron transport chains, NADH cytochrome b5 reductase was not affected by fibrate treatment, NADPH cytochrome c reductase activity was enhanced (BFB = GFB > CFB), whereas NADH cytochrome c reductase activity was reduced by CFB and BFB. 6. The increase in Delta-9 and Delta-5 desaturase activities was highly dependent on the peroxisomal proliferation phenomena, whereas the increase in Delta-6 desaturase activity and the decrease in NADH cytochromec reductase was mainly independent. The modifications of palmitoyl-CoA elongase and NADPH cytochrome c reductase activities, as well as plasma lipid levels, were partially correlated with peroxisomal beta-oxidation, but the r2 values obtained point to the existence of additional independent mechanisms.7. As man is assumed to be a species refractory to peroxisomal proliferation, only those fibrate effectsnot absolutely related to this phenomenon are expected to appear after fibrate therapy.
Alegret
M
M
Dept. Farmacología y Química Terapeutica, Facultad de Farmacia, Núcleo Universitario de Pedralbes, Barcelona, Spain.
Cerqueda
E
E
Ferrando
R
R
Vázquez
M
M
Sánchez
R M
RM
Adzet
T
T
Merlos
M
M
Laguna
J C
JC
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology*; D004041:Dietary Fats / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism*; D015248:Gemfibrozil / Q000494:pharmacology*; D008297:Male; D008830:Microbodies / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004041:Dietary Fats; D005227:Fatty Acids; D044943:Fatty Acid Desaturases; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D002994:Clofibrate; D015248:Gemfibrozil; D001629:Bezafibrate