The influence of pioglitazone on the plasma amino acid profile in patients with nonalcoholic steatohepatitis (NASH)

Background and aims: The peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand, piglitazone, enhances the degradation of branched-chain amino acids (BCAAs) in adipose tissue. However, it remains unknown whether pioglitazone influences the plasma amino acids (AA) profile in patients with nonalcoholic steatohepatitis (NASH). Thus, we investigated the relation between the therapeutic effect and the AA profile in NASH patients with a prospective study. Methods: We randomized 25 histologically proven NASH patients to diet treatment only or diet treatment plus pioglitazone (15 mg/day), and investigated the biological data for 24 months. We measured the concentrations of AAs and compared them between the beginning and the end of the study. Results: Compared with the diet only group, pioglitazone therapy was associated with an increase in body weight (mean change -1.03 vs. +3.8 kg; p = 0.027) and subcutaneous fat (-3.7 vs. +45.7 cm²; p = 0.056), and decreased ALT levels (-0.6 vs. -38.4 IU/L; p = 0.029) and HbA1c (0.33 vs. -0.29 %; p = 0.016). Regarding the AA profile, l-isoleucine, l-leucine, l-histidine, and l-lysine were significantly reduced in patients treated with pioglitazone. Furthermore, l-leucine was significantly reduced compared with those in the diet only group (mean change -34.8 vs. +4.12 nmol/mL; p = 0.032). Interestingly, there was a significant correlation between the changes in BCAAs, especially l-leucine, and those in ALT regardless of treatment with pioglitazone. Conclusions: Pioglitazone therapy in NASH subjects significantly reduced the plasma BCAA level and the degradation was closely related to the improvement of the ALT levels. These results suggest that pioglitazone improves insulin resistance and BCAA metabolism in NASH patients.