PPAR-?-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH

Background and Aims: Peroxisome proliferator-activated receptor (PPAR)-? agonists decrease hepatic/visceral fat (VF) and improve necroinflammation despite subcutaneous (SC) fat weight-gain. Understanding the impact of changes in VF, VF-to-SC fat distribution (VF/SC) and adiponectin (ADPN) levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-? agonists are being developed for treating non-alcoholic steatohepatitis (NASH). Methods: Fifty-five patients with NASH received a -500 kcal/d hypocaloric diet and were randomized (double-blind) to pioglitazone (45 mg/d) or placebo for 6-months. Before and after treatment patients underwent a liver biopsy and measurement of hepatic/peripheral glucose fluxes, hepatic/adipose tissue-IR and, in 35 patients, hepatic and VF/SC-fat was measured by magnetic resonance spectroscopy/imaging. Data were examined by multivariable statistical analyses combined with machine-learning techniques (partial least square discriminant analysis [PLS-DA]). Results: Both pioglitazone (despite weight-gain) and placebo (if weight-loss) reduced steatosis but only pioglitazone ameliorated necroinflammation. Using machine-learning PLS-DA showed that the treatment differences induced by a PPAR-? agonist vs placebo on metabolic variables and liver histology could be best explained by the increase in ADPN and a decrease in VF/SC, and to a lesser degree, improvement in oral glucose tolerance test-glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in ADPN (r = -.71 and r = -.44, P <.007, respectively) and reduction in VF/SC fat (r =.41 and r =.37, P <.03 respectively). Conclusions: Reduction in VF and improved VF/SC-distribution, combined with an increase in ADPN, mediate the histological benefits of PPAR-? action, highlighting the central role of fat metabolism and its distribution on steatohepatitis disease activity in patients with NASH.