TROGLITAZONE INHIBITS FATTY-ACID OXIDATION AND ESTERIFICATION, AND GLUCONEOGENESIS IN ISOLATED HEPATOCYTES FROM STARVED RATS

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rat s. These thiazolidinediones inhibited long-chain fatty acid (oleate) o xidation and produced a very oxidized mitochondrial redox state. By co ntrast, thiazolidinediones did not affect the rate of medium-chain fat ty acid (octanoate) oxidation or the activity of mitochondrial carniti ne palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectiv ely triglyceride synthesis but not phospholipid synthesis. The combine d inhibition of oleate oxidation and esterification by troglitazone wa s due to a noncompetitive inhibition of mitochondrial and microsomal l ong-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative i n liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations s uggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase r eactions. It was concluded that 1) at a similar concentration, troglit azone was more efficient than pioglitazone to inhibit fatty acid metab olism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD(+), and ATP-to-AD P ratios).