Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression.
The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.
Kohl
Claude
C
Endocrinologie et Métabolisme, Institut Cochin, INSERM U567, Paris, France.
Ravel
Denis
D
Girard
Jean
J
Pégorier
Jean-Paul
JP
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism*; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011770:Pyruvate Kinase / Q000235:genetics; D011773:Pyruvates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018490:Serotonin Agents / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D005227:Fatty Acids; D007773:Lactates; D011773:Pyruvates; D012333:RNA, Messenger; D018490:Serotonin Agents; D005277:Fenfluramine; C001584:benfluorex; D000105:Acetyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D006904:Hydroxymethylglutaryl-CoA Synthase; D005941:Glucokinase; D011770:Pyruvate Kinase; D005952:Glucose-6-Phosphatase; D005947:Glucose