Stimulation of fatty acid utilization by sodium clofibrate in rat and monkey hepatocytes.
The acute effects of sodium clofibrate (NaCPIB) on the metabolism of [1-14C]palmitate, [1-14C]octanoate, [1-14C]butyrate, and [2-3H]glycerol by freshly isolated hepatocytes were tested to explore its mechanism of action. Labeled long-, medium-, and short-chain fatty acids were incorporated into all the major lipid classes and were oxidized to 14CO2 by the liver cells. The partitioning of labeled fatty acids from lipogenic towards oxidative pathways was inversely related to fatty acid chain length. [1-14C]Palmitate was incorporated mainly into cellular triglycerides and phospholipids; [1-14C]octanoate, mainly into triglycerides and free cholesterol; and [1-14C]butyrate, mainly into free cholesterol and phospholipids of the cells. NaCPIB (1-3 mM) rapidly stimulated the esterification of labeled palmitate or glycerol to triglycerides, but drug levels greater than 5 mM were inhibitory to esterification. NaCPIB (1 mM) increased the oxidation of [1-14C]palmitate to 14CO2 by either rat or monkey hepatocytes and enhanced the release of labeled lipids from [2-3H]glycerol-prelabeled cells into the extracellular medium. Accelerated [1-14C]octanoate incorporation into glycerolipids and sterols and increased [1-14C]octanoate conversion to 14CO2 were observed in rat liver cells incubated with 1 mM NaCPIB. In contrast, the same drug level stimulated the oxidation of [1-14C]butyrate to 14CO2 but greatly diminished its incorporation into hepatocellular sterols or glycerolipids. These results indicate that (a) NaCPIB acutely alters hepatic ultilization of fatty acids by actions at diverse loci; (b) these metabolic alterations vary with fatty acid chain length; and (c) these effects are probably due to rapid changes in biochemical regulatory mechanism and/or in substrate channelling within the cells. These data further suggest that the early hypolipidemic effect of the drug in rats and primates may be related to an enhanced hepatic oxidation of long-chain fatty acids, but cannot be attributed simply to a reduction in their esterification to complex lipids.
D000818:Animals; D002087:Butyrates / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism; D002245:Carbon Dioxide / Q000096:biosynthesis; D002784:Cholesterol / Q000096:biosynthesis; D002994:Clofibrate / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010168:Palmitates / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D012453:Saimiri; D013268:Stimulation, Chemical; D014280:Triglycerides / Q000096:biosynthesis
D002087:Butyrates; D002210:Caprylates; D005227:Fatty Acids; D010168:Palmitates; D010743:Phospholipids; D014280:Triglycerides; D002245:Carbon Dioxide; D002784:Cholesterol; D002994:Clofibrate