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In Liver international : official journal of the International Association for the Study of the Liver

BACKGROUND&AIMS : PPAR-γ 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 distribution (VF/SC) and adiponectin levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-γ agonists are being developed for treating NASH.

METHODS : Fifty-five patients with NASH received a -500 kcal/day 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 thirty-five 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 (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-γ agonist vs. placebo on metabolic variables and liver histology could be best explained by the increase in adiponectin and a decrease in VF/SC, and to a lesser degree, improvement in OGTT-glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in adiponectin (r=-0.71 and r=-0.44, p< 0.007, respectively) and reduction in VF/SC (r=0.41 and r=0.37, p<0.03, respectively).

CONCLUSIONS : Reduction in VF and improved VF/SC-distribution, combined with an increase in adiponectin, mediate the histological benefits of PPAR-γ action, highlighting the central role of fat metabolism and its distribution on steatohepatitis disease activity in patients with NASH.

Gastaldelli Amalia, Sabatini Silvia, Carli Fabrizia, Gaggini Melania, Bril Fernando, Belfort-DeAguiar Renata, Positano Vincenzo, Barb Diana, Kadiyala Sushma, Harrison Stephen, Cusi Kenneth


NASH, PPAR-g, adiponectin, fatty liver, insulin resistance, non-alcoholic steatohepatitis, pioglitazone, type 2 diabetes mellitus, visceral fat